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University of Rochester
1.
Harder, Jeffrey M.
The Role of Bcl-2 Family Members in Retinal Ganglion Cell
Death.
Degree: PhD, 2013, University of Rochester
URL: http://hdl.handle.net/1802/26812
► Glaucomas are a group of diseases that often lead to blindness. Glaucomas are unified by the characteristic cell death of the output neuron of the…
(more)
▼ Glaucomas are a group of diseases that often lead
to blindness. Glaucomas are unified by
the characteristic cell
death of the output neuron of the retina, the retinal ganglion
cell
(RGC). In glaucoma, axonal injury to RGCs is a key event that
precipitates their death;
however, the molecular mechanisms
leading to RGC death after axonal injury remain
unclear. In fact,
only one molecule, BAX, has been shown to be necessary for
glaucomatous RGC death. BAX is a member of the Bcl-2 family of
apoptotic regulators
and BAX activation is a final step in
triggering apoptosis. Other Bcl-2 family members
can interact with
BAX and regulate its activity. Identifying the Bcl-2 family
members
that mediate BAX activation in RGCs is an important step
toward defining the cell
signaling pathways responsible for RGC
death in glaucoma. This work investigates the
contributions of
Bcl-2 family members implicated in RGC death in vivo using mice
with
specific Bcl-2 family genes deleted.
Based on their
function, the pro-death Bcl-2 family members BIM, BBC3, and BID
are
the primary candidates to mediate BAX activation in RGCs. BAX
activation is highly
potentiated by, if not requires, direct
binding between BAX and these pro-death
molecules. In mice lacking
these genes, RGC death following axonal injury was
significantly
delayed. These experiments uncovered the additive, but hierarchical
nature
of BIM, BBC3, and BID function in RGCs. However, these
molecules were not required
for RGC death after axonal injury.
Although BIM potently induced RGC death after
axonal injury, the
loss of RGCs in a mouse model of pigmentary glaucoma was also not
prevented in a Bim knockout mouse. In RGCs, alternative BAX
activation may occur
following inhibition of pro-survival Bcl-2
family members. BCL-X was identified as an
active endogenous
factor that promotes RGC survival in the adult after axonal
injury.
However, disrupting other pro-death Bcl-2 family members,
who primarily function to
antagonize BCL-X, did not alter RGC
death. The results provide insight into the specific
and
multifaceted nature of BAX activation in RGCs and point to an
important interaction
between pro-survival and pro-death signaling
leading to RGC death in glaucoma.
Subjects/Keywords: Neurodegeneration
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APA ·
Chicago ·
MLA ·
Vancouver ·
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APA (6th Edition):
Harder, J. M. (2013). The Role of Bcl-2 Family Members in Retinal Ganglion Cell
Death. (Doctoral Dissertation). University of Rochester. Retrieved from http://hdl.handle.net/1802/26812
Chicago Manual of Style (16th Edition):
Harder, Jeffrey M. “The Role of Bcl-2 Family Members in Retinal Ganglion Cell
Death.” 2013. Doctoral Dissertation, University of Rochester. Accessed March 04, 2021.
http://hdl.handle.net/1802/26812.
MLA Handbook (7th Edition):
Harder, Jeffrey M. “The Role of Bcl-2 Family Members in Retinal Ganglion Cell
Death.” 2013. Web. 04 Mar 2021.
Vancouver:
Harder JM. The Role of Bcl-2 Family Members in Retinal Ganglion Cell
Death. [Internet] [Doctoral dissertation]. University of Rochester; 2013. [cited 2021 Mar 04].
Available from: http://hdl.handle.net/1802/26812.
Council of Science Editors:
Harder JM. The Role of Bcl-2 Family Members in Retinal Ganglion Cell
Death. [Doctoral Dissertation]. University of Rochester; 2013. Available from: http://hdl.handle.net/1802/26812

Cornell University
2.
Brady, Owen.
Investigating Mechanisms Of Ftld-Tdp Pathogenesis.
Degree: PhD, Molecular and Cell Biology, 2014, Cornell University
URL: http://hdl.handle.net/1813/36146
► Frontotemporal lobar degeneration (FTLD) is a devastating dementia disorder that causes profound changes in personality, behavior, and language abilities. Major breakthroughs in the past decade…
(more)
▼ Frontotemporal lobar degeneration (FTLD) is a devastating dementia disorder that causes profound changes in personality, behavior, and language abilities. Major breakthroughs in the past decade have advanced the understanding of the molecular genetics and pathological mechanisms underlying this disease, in particular the most common subtype, FTLD-TDP. Several causative and risk modifying genes have been identified which implicate defects in protein degradation and RNA metabolism pathways. The work presented here can be split into two main projects. In the first, I examine the physical properties of TDP-43 aggregation, which is a hallmark of FTLDTDP. Specifically, I characterize the role that phosphorylation plays in mediating the aggregation propensity of TDP-43 in a mammalian cell culture system. I further show that TDP-43 aggregates are cleared by the autophagy lysosome and ubiquitin proteasome systems, with the ubiquitin binding adaptor protein, p62/SQSTM1 facilitating this process. In the second project, I sought to characterize the recently identified FTLD-TDP risk factor, TMEM106B. Using cell culture model systems, I demonstrate that TMEM106B overexpression causes specific defects in lysosome size, morphology, and degradative capacity. I also ruled out the effect of a small coding variant associated with the TMEM106B risk allele when the proteins are highly expressed at the same level, indicating that increased TMEM106B levels are the likely cause of defects seen in certain cases of FTLD-TDP. I have also identified a putative degradation pathway implicating lumenal lysosomal enzymes and a membrane bound intramembrane protease, SPPL2a, in the sequential proteolysis of TMEM106B. This pathway may represent a novel therapeutic target for controlling TMEM106B levels in vivo. Overall, my work has contributed significant findings to the field of FTLD-TDP related research and has increased the body of knowledge regarding the cellular and molecular mechanisms that contribute to this terrible disease.
Advisors/Committee Members: Hu, Fenghua (chair), Lin, David M. (committee member), Brown, William J (committee member).
Subjects/Keywords: Neurodegeneration; Lysosomes; TMEM106B
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❌
APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
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APA (6th Edition):
Brady, O. (2014). Investigating Mechanisms Of Ftld-Tdp Pathogenesis. (Doctoral Dissertation). Cornell University. Retrieved from http://hdl.handle.net/1813/36146
Chicago Manual of Style (16th Edition):
Brady, Owen. “Investigating Mechanisms Of Ftld-Tdp Pathogenesis.” 2014. Doctoral Dissertation, Cornell University. Accessed March 04, 2021.
http://hdl.handle.net/1813/36146.
MLA Handbook (7th Edition):
Brady, Owen. “Investigating Mechanisms Of Ftld-Tdp Pathogenesis.” 2014. Web. 04 Mar 2021.
Vancouver:
Brady O. Investigating Mechanisms Of Ftld-Tdp Pathogenesis. [Internet] [Doctoral dissertation]. Cornell University; 2014. [cited 2021 Mar 04].
Available from: http://hdl.handle.net/1813/36146.
Council of Science Editors:
Brady O. Investigating Mechanisms Of Ftld-Tdp Pathogenesis. [Doctoral Dissertation]. Cornell University; 2014. Available from: http://hdl.handle.net/1813/36146

University of Miami
3.
Tseng, LeinWeih Andrew.
Ubiquitylation of Neuronal Pentraxin with Chromo Domain by the E3 Ubiquitin Ligase Mayven/KLHL2 and Effects on Aggresome Formation and Neuronal Cytotoxicity.
Degree: PhD, Molecular and Cellular Pharmacology (Medicine), 2010, University of Miami
URL: https://scholarlyrepository.miami.edu/oa_dissertations/662
► Neuronal pentraxin with chromo domain (NPCD) belongs to a family of neuronally-expressed pentraxin proteins thought to be involved in synaptic refinement and plasticity. One…
(more)
▼ Neuronal pentraxin with chromo domain (NPCD) belongs to a family of neuronally-expressed pentraxin proteins thought to be involved in synaptic refinement and plasticity. One isoform of Npcd, neuronal pentraxin receptor (NPR), is a type-II transmembrane protein responsible for the clustering of related neuronal pentraxins 1 and 2. However, recently identified cytosolic NPCD isoforms with no known function were discovered through their interaction with the intracellular domain of a receptor protein tyrosine phosphatase PTPRO. PTPRO is a signaling molecule known to be involved in the development of the nervous system. Additionally, upregulated expression of neuronal pentraxins has been implicated in neuronal cytotoxicity and associated with neurodegenerative diseases. Here, we demonstrate that a novel cytosolic NPCD isoform interacts with the BTB-Kelch protein Mayven/KLHL2. This interaction was identified through a yeast two-hybrid screen using the C-terminal pentraxin domain region of NPCD and confirmed through mammalian cell colocalization and co-immunoprecipitation studies. Domain truncation analysis suggests that the kelch domains of Mayven/KLHL2 are responsible for this interaction with NPCD. We also show that Mayven/KLHL2 is capable of interacting with Cullin 3, an integral protein in the Cullin-RING ubiquitin ligase complex. An in-vivo ubiquitylation assay demonstrates that overexpression of Mayven/KLHL2 increases NPCD ubiquitylation, and suggests a novel E3 ubiquitin ligase function of Mayven/KLHL2 with NPCD as its substrate. Furthermore, we observed an increased propensity of overexpressed NPCD to form aggresomes with coexpression of Mayven/KLHL2. As the formation of aggresomes is often associated with protein aggregation and deposition diseases, including a multitude of neurodegenerative diseases, we tested NPCD overexpression and the effects of Mayven/KLHL2 coexpression on neuronal cytotoxicity and apoptosis. Overexpressed NPCD in hippocampal neuron cultures resulted in increased cytotoxicity and apoptosis, further exacerbated by Mayven/KLHL2 coexpression. Our findings report an interaction between NPCD and Mayven/KLHL2, demonstrate a novel role of Mayven/KLHL2 as an E3 ubiquitin ligase, and explore a possible intersection between the ubiquitin-proteasome degradation pathway, neuronal pentraxins, and neurodegenerative disease.
Advisors/Committee Members: Fulvia Verde, Sandra Lemmon, Abigail Hackam, John Bixby, Nagi Ayad - Outside Committee Member.
Subjects/Keywords: Protein Aggregation; Neurodegeneration
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❌
APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Tseng, L. A. (2010). Ubiquitylation of Neuronal Pentraxin with Chromo Domain by the E3 Ubiquitin Ligase Mayven/KLHL2 and Effects on Aggresome Formation and Neuronal Cytotoxicity. (Doctoral Dissertation). University of Miami. Retrieved from https://scholarlyrepository.miami.edu/oa_dissertations/662
Chicago Manual of Style (16th Edition):
Tseng, LeinWeih Andrew. “Ubiquitylation of Neuronal Pentraxin with Chromo Domain by the E3 Ubiquitin Ligase Mayven/KLHL2 and Effects on Aggresome Formation and Neuronal Cytotoxicity.” 2010. Doctoral Dissertation, University of Miami. Accessed March 04, 2021.
https://scholarlyrepository.miami.edu/oa_dissertations/662.
MLA Handbook (7th Edition):
Tseng, LeinWeih Andrew. “Ubiquitylation of Neuronal Pentraxin with Chromo Domain by the E3 Ubiquitin Ligase Mayven/KLHL2 and Effects on Aggresome Formation and Neuronal Cytotoxicity.” 2010. Web. 04 Mar 2021.
Vancouver:
Tseng LA. Ubiquitylation of Neuronal Pentraxin with Chromo Domain by the E3 Ubiquitin Ligase Mayven/KLHL2 and Effects on Aggresome Formation and Neuronal Cytotoxicity. [Internet] [Doctoral dissertation]. University of Miami; 2010. [cited 2021 Mar 04].
Available from: https://scholarlyrepository.miami.edu/oa_dissertations/662.
Council of Science Editors:
Tseng LA. Ubiquitylation of Neuronal Pentraxin with Chromo Domain by the E3 Ubiquitin Ligase Mayven/KLHL2 and Effects on Aggresome Formation and Neuronal Cytotoxicity. [Doctoral Dissertation]. University of Miami; 2010. Available from: https://scholarlyrepository.miami.edu/oa_dissertations/662

University of Miami
4.
Tseng, LeinWeih Andrew.
Ubiquitylation of Neuronal Pentraxin with Chromo Domain by the E3 Ubiquitin Ligase Mayven/KLHL2 and Effects on Aggresome Formation and Neuronal Cytotoxicity.
Degree: PhD, Molecular and Cellular Pharmacology (Medicine), 2010, University of Miami
URL: https://scholarlyrepository.miami.edu/oa_dissertations/928
► Neuronal pentraxin with chromo domain (NPCD) belongs to a family of neuronally-expressed pentraxin proteins thought to be involved in synaptic refinement and plasticity. One…
(more)
▼ Neuronal pentraxin with chromo domain (NPCD) belongs to a family of neuronally-expressed pentraxin proteins thought to be involved in synaptic refinement and plasticity. One isoform of Npcd, neuronal pentraxin receptor (NPR), is a type-II transmembrane protein responsible for the clustering of related neuronal pentraxins 1 and 2. However, recently identified cytosolic NPCD isoforms with no known function were discovered through their interaction with the intracellular domain of a receptor protein tyrosine phosphatase PTPRO. PTPRO is a signaling molecule known to be involved in the development of the nervous system. Additionally, upregulated expression of neuronal pentraxins has been implicated in neuronal cytotoxicity and associated with neurodegenerative diseases. Here, we demonstrate that a novel cytosolic NPCD isoform interacts with the BTB-Kelch protein Mayven/KLHL2. This interaction was identified through a yeast two-hybrid screen using the C-terminal pentraxin domain region of NPCD and confirmed through mammalian cell colocalization and co-immunoprecipitation studies. Domain truncation analysis suggests that the kelch domains of Mayven/KLHL2 are responsible for this interaction with NPCD. We also show that Mayven/KLHL2 is capable of interacting with Cullin 3, an integral protein in the Cullin-RING ubiquitin ligase complex. An in-vivo ubiquitylation assay demonstrates that overexpression of Mayven/KLHL2 increases NPCD ubiquitylation, and suggests a novel E3 ubiquitin ligase function of Mayven/KLHL2 with NPCD as its substrate. Furthermore, we observed an increased propensity of overexpressed NPCD to form aggresomes with coexpression of Mayven/KLHL2. As the formation of aggresomes is often associated with protein aggregation and deposition diseases, including a multitude of neurodegenerative diseases, we tested NPCD overexpression and the effects of Mayven/KLHL2 coexpression on neuronal cytotoxicity and apoptosis. Overexpressed NPCD in hippocampal neuron cultures resulted in increased cytotoxicity and apoptosis, further exacerbated by Mayven/KLHL2 coexpression. Our findings report an interaction between NPCD and Mayven/KLHL2, demonstrate a novel role of Mayven/KLHL2 as an E3 ubiquitin ligase, and explore a possible intersection between the ubiquitin-proteasome degradation pathway, neuronal pentraxins, and neurodegenerative disease.
Advisors/Committee Members: Fulvia Verde, Sandra Lemmon, Abigail Hackam, John Bixby, Nagi Ayad.
Subjects/Keywords: Protein Aggregation; Neurodegeneration
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❌
APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Tseng, L. A. (2010). Ubiquitylation of Neuronal Pentraxin with Chromo Domain by the E3 Ubiquitin Ligase Mayven/KLHL2 and Effects on Aggresome Formation and Neuronal Cytotoxicity. (Doctoral Dissertation). University of Miami. Retrieved from https://scholarlyrepository.miami.edu/oa_dissertations/928
Chicago Manual of Style (16th Edition):
Tseng, LeinWeih Andrew. “Ubiquitylation of Neuronal Pentraxin with Chromo Domain by the E3 Ubiquitin Ligase Mayven/KLHL2 and Effects on Aggresome Formation and Neuronal Cytotoxicity.” 2010. Doctoral Dissertation, University of Miami. Accessed March 04, 2021.
https://scholarlyrepository.miami.edu/oa_dissertations/928.
MLA Handbook (7th Edition):
Tseng, LeinWeih Andrew. “Ubiquitylation of Neuronal Pentraxin with Chromo Domain by the E3 Ubiquitin Ligase Mayven/KLHL2 and Effects on Aggresome Formation and Neuronal Cytotoxicity.” 2010. Web. 04 Mar 2021.
Vancouver:
Tseng LA. Ubiquitylation of Neuronal Pentraxin with Chromo Domain by the E3 Ubiquitin Ligase Mayven/KLHL2 and Effects on Aggresome Formation and Neuronal Cytotoxicity. [Internet] [Doctoral dissertation]. University of Miami; 2010. [cited 2021 Mar 04].
Available from: https://scholarlyrepository.miami.edu/oa_dissertations/928.
Council of Science Editors:
Tseng LA. Ubiquitylation of Neuronal Pentraxin with Chromo Domain by the E3 Ubiquitin Ligase Mayven/KLHL2 and Effects on Aggresome Formation and Neuronal Cytotoxicity. [Doctoral Dissertation]. University of Miami; 2010. Available from: https://scholarlyrepository.miami.edu/oa_dissertations/928

University of Melbourne
5.
Welton, Jeremy Morris.
Therapeutic implications in genetic prion disease.
Degree: 2011, University of Melbourne
URL: http://hdl.handle.net/11343/37643
► Prion diseases are fatal neurodegenerative diseases caused by the misfolding of the prion protein (PrP). Of the three subsets of prion diseases (sporadic, genetic, acquired),…
(more)
▼ Prion diseases are fatal neurodegenerative diseases caused by the misfolding of the prion protein (PrP). Of the three subsets of prion diseases (sporadic, genetic, acquired), genetic prion disease is associated with a mutation of PrP, leading to an increased disposition for the mutant PrP to misfold, and adopt a disease associated conformation (PrPD ). The following project investigated how a mutation of the prion protein, the P102L mutation, affected the disease associated properties of PrP and the impact of this mutation upon therapeutic outcome.
The 102L and 101L mutation were introduced into human and mouse PrP respectively and expressed in rabbit kidney epithelial (RK13) cells to further investigate the effect of this mutation on the prion protein, and the outcome of prion infection. The 102L and 101L mutant PrP produced by RK13 cells was found to increase the disease associated characteristics of human and mouse PrP. Mutant PrP was also found to enhance the binding of PrP to glycosaminoglycans, a cofactor potentially involved in conversion of PrPC to PrPD . The human and mouse PrP expressing RK13 cell with or without the 102L/101L mutation were exposed to several human and mouse strains of prions to determine the susceptibility of the cells to prion infection. Prion infection of RK13 cells expressing 102P or 102L human PrP (huPrP) was not observed. RK13 cells expressing 101L mouse PrP (moPrP) were more susceptible to infection from two strains of prions, compared with 101P moPrP expressing RK13 cells. The enhanced susceptibility of 101L moPrP expressing RK13 (moRK13) cells was determined to be due to increased uptake of protease resistant PrP (PrPres ), mediated aberrant glycosaminoglycan binding.
The therapeutic efficacy of glycosaminoglycan based therapy was investigated in the 101L model of genetic prion disease to determine if the enhanced binding of 101L moPrP affected the therapeutic action. Investigation of the membrane localisation of 101P and 101L moPrP by subcellular fractionation identified a subtle difference between 101P and 101L moPrP. A reduction in the proportion of 101L moPrP was detected in the lipid raft associated fractions compared with 101P moPrP, suggesting that a population of 101L moPrP is aberrantly located in another membrane domain or intracellular compartment.
The results of the study suggest that the enhanced binding of 101L moPrP to glycosaminoglycans mediates the association of 101L PrP in an aberrant membrane domain, and mediates conversion of 101L moPrP to PrPres in spite of treatment with glycosaminoglycan or lipid raft altering therapeutics.
The prophylactic treatment of persons found to have pathogenic mutations associated with genetic prion disease provides the best opportunity of intervening in prion disease progression, more-so than sporadic and acquired forms of prion disease which are…
Subjects/Keywords: neurodegeneration; prion; P102L
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❌
APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Welton, J. M. (2011). Therapeutic implications in genetic prion disease. (Doctoral Dissertation). University of Melbourne. Retrieved from http://hdl.handle.net/11343/37643
Chicago Manual of Style (16th Edition):
Welton, Jeremy Morris. “Therapeutic implications in genetic prion disease.” 2011. Doctoral Dissertation, University of Melbourne. Accessed March 04, 2021.
http://hdl.handle.net/11343/37643.
MLA Handbook (7th Edition):
Welton, Jeremy Morris. “Therapeutic implications in genetic prion disease.” 2011. Web. 04 Mar 2021.
Vancouver:
Welton JM. Therapeutic implications in genetic prion disease. [Internet] [Doctoral dissertation]. University of Melbourne; 2011. [cited 2021 Mar 04].
Available from: http://hdl.handle.net/11343/37643.
Council of Science Editors:
Welton JM. Therapeutic implications in genetic prion disease. [Doctoral Dissertation]. University of Melbourne; 2011. Available from: http://hdl.handle.net/11343/37643

University of Arizona
6.
Coyne, Alyssa N.
Dysregulation of mRNA Transport and Translation in ALS
.
Degree: 2016, University of Arizona
URL: http://hdl.handle.net/10150/623181
► Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disease affecting upper and lower motor neurons. Although many cellular processes such as cytoskeletal maintenance and synaptic…
(more)
▼ Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disease affecting upper and lower motor neurons. Although many cellular processes such as cytoskeletal maintenance and synaptic function are disrupted in ALS, the molecular mechanisms by which these defects arise remain poorly understood. TDP-43, an RNA binding protein linked to the majority of ALS cases, is involved in multiple aspects of RNA metabolism. It is hypothesized that TDP-43 may sequester its mRNA targets into cytoplasmic stress granules during disease progression in turn, inhibiting their localization and/or translation. This work uses a Drosophila model of ALS based on TDP-43, to provide evidence for TDP-43’s role in translation regulation of specific mRNA targets. Using a combination of genetic, molecular, and imaging approaches this work has identified TDP-43 induced post-transcriptional alterations in futsch and hsc70-4 mRNAs. First, futsch/MAP1B is a TDP-43 mRNA target altered at the level of mRNA localization and translation. This results in microtubule instability at the NMJ as evidenced by an increased number of satellite boutons and decreased number of Futsch positive loops that are thought to indicate stable synaptic contacts. Furthermore, overexpression of Futsch mitigates defects in microtubule stability and TDP-43 dependent locomotor dysfunction and also increases lifespan. Second, this work shows that synaptic expression of Hsc70-4, a molecular chaperone critical for synaptic vesicle cycling is involved in multiple steps of the synaptic vesicle cycle, is reduced at the NMJ when TDP-43 is overexpressed in motor neurons. Using a combination of electrophysiology and FM1-43 dye uptake assays, this work shows that motor neuron expression of TDP-43 induces defects in synaptic vesicle endocytosis. Third, this work identifies Fragile X Protein (FMRP) as a neuroprotective protein partner of TDP-43. FMRP overexpression remodels RNP granules, extracts TDP-43 from insoluble complexes, and restores the translation of specific TDP-43 targets. Together, these data provides evidence for translation dysregulation underlying microtubule instability and synaptic dysfunction in ALS pathogenesis and identifies restoration of translation via remodeling RNP granules as a neuroprotective strategy to mitigate toxicity.
Advisors/Committee Members: Zarnescu, Daniela C (advisor), Zarnescu, Daniela C. (committeemember), Zinsmaier, Konrad (committeemember), Buchan, John (committeemember), Madhavan, Lalitha (committeemember).
Subjects/Keywords: Drosophila;
neurodegeneration;
ALS
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❌
APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Coyne, A. N. (2016). Dysregulation of mRNA Transport and Translation in ALS
. (Doctoral Dissertation). University of Arizona. Retrieved from http://hdl.handle.net/10150/623181
Chicago Manual of Style (16th Edition):
Coyne, Alyssa N. “Dysregulation of mRNA Transport and Translation in ALS
.” 2016. Doctoral Dissertation, University of Arizona. Accessed March 04, 2021.
http://hdl.handle.net/10150/623181.
MLA Handbook (7th Edition):
Coyne, Alyssa N. “Dysregulation of mRNA Transport and Translation in ALS
.” 2016. Web. 04 Mar 2021.
Vancouver:
Coyne AN. Dysregulation of mRNA Transport and Translation in ALS
. [Internet] [Doctoral dissertation]. University of Arizona; 2016. [cited 2021 Mar 04].
Available from: http://hdl.handle.net/10150/623181.
Council of Science Editors:
Coyne AN. Dysregulation of mRNA Transport and Translation in ALS
. [Doctoral Dissertation]. University of Arizona; 2016. Available from: http://hdl.handle.net/10150/623181

University of Manchester
7.
Howard, Daniel.
The role of the cytoskeleton in Alzheimer’s disease: a
Drosophila perspective.
Degree: 2016, University of Manchester
URL: http://www.manchester.ac.uk/escholar/uk-ac-man-scw:300556
► Alzheimer’s disease (AD) pathogenesis is likely to be caused by dysfunction of two neuronal proteins, amyloid-beta (Aβ) and tau. Whilst excellent in vivo assays have…
(more)
▼ Alzheimer’s disease (AD) pathogenesis is likely to
be caused by dysfunction of two neuronal proteins, amyloid-beta
(Aβ) and tau. Whilst excellent in vivo assays have been performed,
and animal models which develop pathology which resembles AD have
been generated, the cellular events that lead to
neurodegeneration
remain poorly understood, in particular those which involve the
cytoskeleton. Microtubules (MTs) are vital for many axonal
functions, including growth and transport. MTs have been implicated
in
neurodegeneration; 44% of cytoskeletal genes have OMIM links to
human disorders, and over half of those disorders result in
neuronal dysfunction. Aβ and tau are well understood biochemically,
but the functional links between these proteins, and how they cause
neurodegeneration, remain poorly understood. In the context of AD,
Aβ and tau are known to have numerous toxic effects which could
have extensive influence on the function of the cytoskeleton; a
system which is essential in neurons. Here I utilise Drosophila
primary neuron culture in order to determine the subcellular
phenotypes associated with the application of Aβ via different
genetic and artificial means, in concert with human tau (hTau), in
a comparative analysis. I have demonstrated that fly neuron culture
is suited in this capacity, and have demonstrated that different
methods of Aβ and hTau application to neurons elicit different
phenotypes, in particular regarding the timing and extent of MT
disorganisation, and suggest that there may be qualitative reasons
for the different phenotypes between the approaches
taken.
Advisors/Committee Members: DOIG, ANDREW AJ, Doig, Andrew, Prokop, Andreas.
Subjects/Keywords: drosophila; neurodegeneration; amyloid; tau
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❌
APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Howard, D. (2016). The role of the cytoskeleton in Alzheimer’s disease: a
Drosophila perspective. (Doctoral Dissertation). University of Manchester. Retrieved from http://www.manchester.ac.uk/escholar/uk-ac-man-scw:300556
Chicago Manual of Style (16th Edition):
Howard, Daniel. “The role of the cytoskeleton in Alzheimer’s disease: a
Drosophila perspective.” 2016. Doctoral Dissertation, University of Manchester. Accessed March 04, 2021.
http://www.manchester.ac.uk/escholar/uk-ac-man-scw:300556.
MLA Handbook (7th Edition):
Howard, Daniel. “The role of the cytoskeleton in Alzheimer’s disease: a
Drosophila perspective.” 2016. Web. 04 Mar 2021.
Vancouver:
Howard D. The role of the cytoskeleton in Alzheimer’s disease: a
Drosophila perspective. [Internet] [Doctoral dissertation]. University of Manchester; 2016. [cited 2021 Mar 04].
Available from: http://www.manchester.ac.uk/escholar/uk-ac-man-scw:300556.
Council of Science Editors:
Howard D. The role of the cytoskeleton in Alzheimer’s disease: a
Drosophila perspective. [Doctoral Dissertation]. University of Manchester; 2016. Available from: http://www.manchester.ac.uk/escholar/uk-ac-man-scw:300556

Vanderbilt University
8.
Ward, Nicholas John.
The Transient Receptor Potential Vanilloid-1 Channel and Neuronal Survival in Degenerative Disease.
Degree: PhD, Neuroscience, 2014, Vanderbilt University
URL: http://hdl.handle.net/1803/13386
► Neuronal responses to stress are an important component of neurodegenerative disease and may represent targets for therapeutic intervention. In normal and pathogenic physiological conditions, members…
(more)
▼ Neuronal responses to stress are an important component of neurodegenerative disease and may represent targets for therapeutic intervention. In normal and pathogenic physiological conditions, members of the transient receptor potential (TRP) family of cation channels have been implicated in transducing stress-related stimuli. Studies detailed in this document characterize the response of the vanilloid-1 TRP channel (TRPV1) to stress from elevated intraocular pressure (IOP) in a mouse model of glaucomatous optic neuropathy. Knockout of TRPV1 (<i>Trpv1</i>-/-) resulted in accelerated degeneration of retinal ganglion cells (RGCs) with elevated IOP. Compared to C57 controls, <i>Trpv1</i>-/- mice exhibited more extensive pathology in terms of axonal transport deficits, loss of RGC axons within the optic nerve, and loss of RGC somas in the retina. This accelerated pathology indicates that TRPV1 may mediate important survival mechanisms in response to IOP-induced stress of RGCs. Soon after IOP elevation, TRPV1 protein levels transiently increase within a layer of the retina associated with RGC dendrites and synapses. Likewise, TRPV1 localization near RGC synaptic active zones increases with IOP-induced stress, indicating a potential influence of TRPV1 on synaptic activity. Morphological studies of RGC dendrites demonstrated that TRPV1 does influence dendritic complexity, indicating a potential role for TRPV1 at synaptic sites in dendrites. The data indicate that TRPV1 may help RGCs survive in response to stress by influencing activity at RGC synapses.
Advisors/Committee Members: David Calkins (committee member), Rebecca Sappington (committee member), Kevin Schey (committee member), Bruce Carter (Committee Chair).
Subjects/Keywords: neurodegeneration; glaucoma; TRPV1; TRP channels
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APA (6th Edition):
Ward, N. J. (2014). The Transient Receptor Potential Vanilloid-1 Channel and Neuronal Survival in Degenerative Disease. (Doctoral Dissertation). Vanderbilt University. Retrieved from http://hdl.handle.net/1803/13386
Chicago Manual of Style (16th Edition):
Ward, Nicholas John. “The Transient Receptor Potential Vanilloid-1 Channel and Neuronal Survival in Degenerative Disease.” 2014. Doctoral Dissertation, Vanderbilt University. Accessed March 04, 2021.
http://hdl.handle.net/1803/13386.
MLA Handbook (7th Edition):
Ward, Nicholas John. “The Transient Receptor Potential Vanilloid-1 Channel and Neuronal Survival in Degenerative Disease.” 2014. Web. 04 Mar 2021.
Vancouver:
Ward NJ. The Transient Receptor Potential Vanilloid-1 Channel and Neuronal Survival in Degenerative Disease. [Internet] [Doctoral dissertation]. Vanderbilt University; 2014. [cited 2021 Mar 04].
Available from: http://hdl.handle.net/1803/13386.
Council of Science Editors:
Ward NJ. The Transient Receptor Potential Vanilloid-1 Channel and Neuronal Survival in Degenerative Disease. [Doctoral Dissertation]. Vanderbilt University; 2014. Available from: http://hdl.handle.net/1803/13386

Boston University
9.
Bleiberg, Benjamin Aaron.
Evaluating the concordance of N-terminal and full length Huntington's disease modifiers and identifying potential therapeutic targets in Drosophila.
Degree: MS, Medical Sciences, 2016, Boston University
URL: http://hdl.handle.net/2144/16770
► Huntington’s disease (HD) is one of nine polyglutamine diseases and it is caused by a CAG expansion in the HTT gene. HD is an autosomal,…
(more)
▼ Huntington’s disease (HD) is one of nine polyglutamine diseases and it is caused by a CAG expansion in the HTT gene. HD is an autosomal, dominantly inherited neurodegenerative disease affecting between 2 and 5 individuals per 100,000 worldwide and it is currently untreatable. HD spreads from the striatum to the rest of the brain and causes widespread motor, cognitive, and psychiatric symptoms, including Huntington’s chorea.
A fruitful approach to identifying potential therapeutic targets for HD is to modify genes in a model organism in an unbiased manner and screen the effect by testing the model in a functional assay. Drosophila models of HD have emerged as key tools for these large scale genetic screens thanks to their combination of ease of maintenance, and breeding in large numbers and their ability to be tested neurobehaviorally.
During the course of HD pathogenesis in mammals, the FL-HTT protein is cleaved by many proteases including caspase-6. This cleavage leads to the co-existence of N-terminal (NT) as well as full-length (FL) forms of mutant HTT in the HD neurons. Drosophila lacks caspase-6 therefore FL-HTT is not naturally cleaved at its target site, this allows us to express either the FL mutant HTT or its cleaved NT fragment independently to characterize their differential pathogenic contribution.
This study aims to test the concordance of a sample of 75 NT-HTT modifiers identified through a directed screen by testing them in a FL-HTT model. In doing so, we hope to identify shared modifiers and shared functional genetic networks, which may be particularly central to HD progression and useful areas in which to discover therapeutic targets. Further, this study may help to determine what types of models are necessary for future screens to adequately understand the genetic networks that underpin HD progression.
In order to assess the impact of the modifier, flies expressing both the modifier and FL-HTT were tested in a climbing assay that measures motor function taking advantage of the model’s innate negative geotactic behavior. Motor performance is measured as the percentage of flies of each genotype that climb up to a 9 cm threshold in a given time interval. Flies were tested at 6 time points on days 18, 19, 20, 21, 22, and 25 of age in order to observe their level of neurobehavioral function in comparison to a positive control of flies with FL-HTT and no modifier and a negative control of flies without mutant HTT.
When NT modifiers were tested in the FL model, there was an enrichment in modifiers relative to what is seen by chance. The NT suppressor sample was significantly enriched in modifier genes that effected motor performance in the FL model. Meanwhile, NT HD enhancers were not enriched with modifiers in the FL model. Some modifiers demonstrated contradictory effects on motor performance depending on the HD model tested. This could be caused by different mechanisms of toxicity inherent to NT versus FL HD or from secondary toxicity as the FL experiment occurred over a longer time period…
Subjects/Keywords: Medicine; Drosophila; Neurodegeneration; Huntington's disease
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APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
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APA (6th Edition):
Bleiberg, B. A. (2016). Evaluating the concordance of N-terminal and full length Huntington's disease modifiers and identifying potential therapeutic targets in Drosophila. (Masters Thesis). Boston University. Retrieved from http://hdl.handle.net/2144/16770
Chicago Manual of Style (16th Edition):
Bleiberg, Benjamin Aaron. “Evaluating the concordance of N-terminal and full length Huntington's disease modifiers and identifying potential therapeutic targets in Drosophila.” 2016. Masters Thesis, Boston University. Accessed March 04, 2021.
http://hdl.handle.net/2144/16770.
MLA Handbook (7th Edition):
Bleiberg, Benjamin Aaron. “Evaluating the concordance of N-terminal and full length Huntington's disease modifiers and identifying potential therapeutic targets in Drosophila.” 2016. Web. 04 Mar 2021.
Vancouver:
Bleiberg BA. Evaluating the concordance of N-terminal and full length Huntington's disease modifiers and identifying potential therapeutic targets in Drosophila. [Internet] [Masters thesis]. Boston University; 2016. [cited 2021 Mar 04].
Available from: http://hdl.handle.net/2144/16770.
Council of Science Editors:
Bleiberg BA. Evaluating the concordance of N-terminal and full length Huntington's disease modifiers and identifying potential therapeutic targets in Drosophila. [Masters Thesis]. Boston University; 2016. Available from: http://hdl.handle.net/2144/16770

University of Cambridge
10.
Sohail, Anood.
Visualizing Roles of Spastic Paraplegia Proteins in Organizing Axonal ER in Live Drosophila.
Degree: PhD, 2019, University of Cambridge
URL: https://www.repository.cam.ac.uk/handle/1810/290113
► Axons possess a continuous network of smooth tubular endoplasmic reticulum (ER), extending from the nuclear envelope throughout the neuron to synapses. Mutations affecting proteins with…
(more)
▼ Axons possess a continuous network of smooth tubular endoplasmic reticulum (ER), extending from the nuclear envelope throughout the neuron to synapses. Mutations affecting proteins with intramembrane hairpin domains that model tubular ER membrane can lead to the axon degenerative disease, hereditary spastic paraplegia (HSP). However, the extent and mechanisms by which HSP proteins contribute to axonal ER organization and dynamics are unclear.
To understand these mechanisms, there is a need to visualize axonal ER in wild-type and mutant live axons. I have therefore aimed to develop these tools in Drosophila larvae and adults, and use them to visualize mutant phenotypes. Firstly, I developed a system to visualize fluorescently marked ER in individual axons in adult fly legs, and tested how this can be used to investigate the effects of loss of intramembrane hairpin HSP proteins on ER in adult legs. Secondly, known mutations affecting HSP hairpin proteins reduce the axonal ER network but not severely; I hypothesized that additional HSP ER membrane proteins might contribute to residual tubule formation; these include Arl6IP, also reported to promote ER tubule formation. I generated transgenic flies to overexpress a fluorescently tagged eGFP::Arl6IP1, and found that this fusion protein localizes within axonal ER.
To study whether loss of Arl6IP1 function affects axonal ER, I tested the effects of knockdown on this compartment, but found no consistent effects. To achieve stronger loss of function, I also generated a mutant stock that lacked one of the transmembrane domains and showed a slight developmental delay in homozygous Drosophila larvae. Like mutations in a number of other HSP hairpin proteins, this lesion is homozygous viable, and further characterization of its phenotype will help elucidate how Arl6IP1 contributes to modeling the axonal ER network.
In conclusion, my work shows the utility of GFP markers of axonal ER, it can facilitate faster screening for other genes that potentially regulate ER structure and for ageing phenotypes that are not apparent in larval stages, and suggests Arl6IP1 as another HSP protein with a role in axonal ER organization.
Subjects/Keywords: Axonal ER; neurodegeneration; drosophila
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APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Sohail, A. (2019). Visualizing Roles of Spastic Paraplegia Proteins in Organizing Axonal ER in Live Drosophila. (Doctoral Dissertation). University of Cambridge. Retrieved from https://www.repository.cam.ac.uk/handle/1810/290113
Chicago Manual of Style (16th Edition):
Sohail, Anood. “Visualizing Roles of Spastic Paraplegia Proteins in Organizing Axonal ER in Live Drosophila.” 2019. Doctoral Dissertation, University of Cambridge. Accessed March 04, 2021.
https://www.repository.cam.ac.uk/handle/1810/290113.
MLA Handbook (7th Edition):
Sohail, Anood. “Visualizing Roles of Spastic Paraplegia Proteins in Organizing Axonal ER in Live Drosophila.” 2019. Web. 04 Mar 2021.
Vancouver:
Sohail A. Visualizing Roles of Spastic Paraplegia Proteins in Organizing Axonal ER in Live Drosophila. [Internet] [Doctoral dissertation]. University of Cambridge; 2019. [cited 2021 Mar 04].
Available from: https://www.repository.cam.ac.uk/handle/1810/290113.
Council of Science Editors:
Sohail A. Visualizing Roles of Spastic Paraplegia Proteins in Organizing Axonal ER in Live Drosophila. [Doctoral Dissertation]. University of Cambridge; 2019. Available from: https://www.repository.cam.ac.uk/handle/1810/290113

University of Debrecen
11.
Seo, Woo Sung.
Role of p53 and PARP-1 in neurodegenerative diseases
.
Degree: DE – Általános Orvostudományi Kar, University of Debrecen
URL: http://hdl.handle.net/2437/243137
► The thesis presents a general review of major neurodegenerative diseases and also discusses the role of p53 and PARP-1 in neurodegeneration. p53 and PARP-1 are…
(more)
▼ The thesis presents a general review of major neurodegenerative diseases and also discusses the role of p53 and PARP-1 in
neurodegeneration. p53 and PARP-1 are 2 very essential proteins involved in cell-cycle regulation, cell death, DNA repair etc. Their role should be elucidated further to understand the pathomechanism but also protection against
neurodegeneration.
Advisors/Committee Members: Hortobágyi, Tibor (advisor), Debreceni Egyetem::Általános Orvostudományi Kar::Pathológiai Intézet (advisor).
Subjects/Keywords: Neurodegeneration;
neuroscience
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APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Seo, W. S. (n.d.). Role of p53 and PARP-1 in neurodegenerative diseases
. (Thesis). University of Debrecen. Retrieved from http://hdl.handle.net/2437/243137
Note: this citation may be lacking information needed for this citation format:
No year of publication.
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Seo, Woo Sung. “Role of p53 and PARP-1 in neurodegenerative diseases
.” Thesis, University of Debrecen. Accessed March 04, 2021.
http://hdl.handle.net/2437/243137.
Note: this citation may be lacking information needed for this citation format:
No year of publication.
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Seo, Woo Sung. “Role of p53 and PARP-1 in neurodegenerative diseases
.” Web. 04 Mar 2021.
Note: this citation may be lacking information needed for this citation format:
No year of publication.
Vancouver:
Seo WS. Role of p53 and PARP-1 in neurodegenerative diseases
. [Internet] [Thesis]. University of Debrecen; [cited 2021 Mar 04].
Available from: http://hdl.handle.net/2437/243137.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
No year of publication.
Council of Science Editors:
Seo WS. Role of p53 and PARP-1 in neurodegenerative diseases
. [Thesis]. University of Debrecen; Available from: http://hdl.handle.net/2437/243137
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
No year of publication.

University of Manitoba
12.
Acosta, Crystal May R.
Antigenic induction of nerve growth factor (NGF) in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS).
Degree: Pharmacy, 2013, University of Manitoba
URL: http://hdl.handle.net/1993/23504
► Nerve growth factor (NGF) represents a new therapeutic strategy for multiple sclerosis (MS) because of its immunomodulatory and neuroprotective activity. To analyze changes in NGF…
(more)
▼ Nerve growth factor (NGF) represents a new therapeutic strategy for multiple sclerosis (MS) because of its immunomodulatory and neuroprotective activity. To analyze changes in NGF expression experimental autoimmune encephalomyelitis (EAE) was induced in Lewis rats. In the dorsal root ganglia (DRG) of animals with EAE, NGF mRNA and protein increased between 18 - 24 days post induction (dpi) during complete neurological recovery. In the spinal cord (SC) of animals with EAE, NGF mRNA and protein expression increased at 15 dpi and 12 dpi, respectively, to reduce EAE-induced disability. We identified the 25 kDa pro-NGF as a biologically active isoform during EAE. EAE SC axons demonstrate a loss or thinning of myelin which correlated with maximal neurological disability. NGF plays a role in minimizing EAE-induced inflammation and myelin damage to promote neurological recovery. NGF may be an “off switch” for a cytokine-neurotrophin signaling triad to govern the extent of myelin damage.
Advisors/Committee Members: Namaka, Mike (Pharmacy) (supervisor), MacNeil, Brian (Medical Rehabilitation) Burczynski, Frank (Pharmacy) (examiningcommittee).
Subjects/Keywords: MS; NGF; Neurodegeneration; Neuroimmunology
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MLA ·
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Export
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APA (6th Edition):
Acosta, C. M. R. (2013). Antigenic induction of nerve growth factor (NGF) in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). (Masters Thesis). University of Manitoba. Retrieved from http://hdl.handle.net/1993/23504
Chicago Manual of Style (16th Edition):
Acosta, Crystal May R. “Antigenic induction of nerve growth factor (NGF) in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS).” 2013. Masters Thesis, University of Manitoba. Accessed March 04, 2021.
http://hdl.handle.net/1993/23504.
MLA Handbook (7th Edition):
Acosta, Crystal May R. “Antigenic induction of nerve growth factor (NGF) in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS).” 2013. Web. 04 Mar 2021.
Vancouver:
Acosta CMR. Antigenic induction of nerve growth factor (NGF) in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). [Internet] [Masters thesis]. University of Manitoba; 2013. [cited 2021 Mar 04].
Available from: http://hdl.handle.net/1993/23504.
Council of Science Editors:
Acosta CMR. Antigenic induction of nerve growth factor (NGF) in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). [Masters Thesis]. University of Manitoba; 2013. Available from: http://hdl.handle.net/1993/23504

University of Edinburgh
13.
Vincenti, James Edward.
Role of activation of microglia in neurodegenerative prion disease.
Degree: PhD, 2015, University of Edinburgh
URL: http://hdl.handle.net/1842/15928
► Prion diseases are a group of fatal neurodegenerative protein-misfolding diseases. Microglia, the resident myeloid cells found within the brain, have been shown to demonstrate a…
(more)
▼ Prion diseases are a group of fatal neurodegenerative protein-misfolding diseases. Microglia, the resident myeloid cells found within the brain, have been shown to demonstrate a reactive morphology during the disease process with conflicting evidence for both a neurotoxic and neuroprotective role. The studies presented here aimed to investigate the role of microglia activation using transcriptomic and morphological analysis of prion disease in mice. Initially, the host immune response to prion disease was explored using a publically available mouse prion disease dataset. Re-analysis of this dataset was performed using BioLayout Express3D; a novel software tool that supports the visualisation and clustering of correlation networks. Disease-associated genes up-regulated during the later stages of infection were present in two main clusters. The cellular origin of these genes was explored by examining their expression in a dataset comprised of pure populations of cells. This demonstrated that the primary cluster of up-regulated transcripts encompassed genes expressed mainly by microglia and to a lesser extent astrocytes and neurons. The secondary cluster comprised almost exclusively of interferon response genes. The conclusions of these analyses were different from those of the original study that suggested disease-associated genes were primarily neuronal in origin. Mouse models of prion disease were established by infecting a novel line of BALB/cJ inbred mice, expressing EGFP under control of a myeloid specific Csf1r promoter, with the 79A prion strain. Quantification of the morphological changes of EGFP expressing microglia suggested the cells accumulated in the medulla at sites of early misfolded protein deposition with minimal change in their overall appearance. An activated microglia morphology was not observed until protein deposition was extensive. Isolation of EGFP expressing microglia was performed for transcriptome analysis. The vast majority of disease associated genes demonstrated increased expression at the onset of clinical symptoms. The gene list was found to be highly enriched for genes associated with an innate immune response regulated by the NFκB signalling cascade. Also highly enriched were processes associated with protein translation, energy production and stress response. These data suggest a high metabolic load is burdened by proliferating microglia; and as part of a response which is strikingly more pro-inflammatory in nature than has previously been attributed to the microglia phenotype within prion disease. As an active contributor to normal homeostasis, microglia are more than just innate immune surveillance and are now considered an integral component in both the healthy and diseased brain. The ramifications of activation toward the microglia phenotype shown here will have direct and potentially cytotoxic influence on neighbouring microglia and other brain cell types implying microglia as major contributors to the neurotoxic environment found within the CNS during prion disease. Furthermore…
Subjects/Keywords: 612.8; microglia; neurodegeneration; neuroimmunology; prion
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MLA ·
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Export
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APA (6th Edition):
Vincenti, J. E. (2015). Role of activation of microglia in neurodegenerative prion disease. (Doctoral Dissertation). University of Edinburgh. Retrieved from http://hdl.handle.net/1842/15928
Chicago Manual of Style (16th Edition):
Vincenti, James Edward. “Role of activation of microglia in neurodegenerative prion disease.” 2015. Doctoral Dissertation, University of Edinburgh. Accessed March 04, 2021.
http://hdl.handle.net/1842/15928.
MLA Handbook (7th Edition):
Vincenti, James Edward. “Role of activation of microglia in neurodegenerative prion disease.” 2015. Web. 04 Mar 2021.
Vancouver:
Vincenti JE. Role of activation of microglia in neurodegenerative prion disease. [Internet] [Doctoral dissertation]. University of Edinburgh; 2015. [cited 2021 Mar 04].
Available from: http://hdl.handle.net/1842/15928.
Council of Science Editors:
Vincenti JE. Role of activation of microglia in neurodegenerative prion disease. [Doctoral Dissertation]. University of Edinburgh; 2015. Available from: http://hdl.handle.net/1842/15928

University of Cambridge
14.
Zhu, Ye.
Studies on the autophagy gene WIPI4 and its interactor UBR5.
Degree: PhD, 2020, University of Cambridge
URL: https://www.repository.cam.ac.uk/handle/1810/300658
► Autophagy is a tightly regulated process that sequesters and delivers proteins and other cellular substances for degradation in the lysosome. Dysfunction of autophagy has been…
(more)
▼ Autophagy is a tightly regulated process that sequesters and delivers proteins and other cellular substances for degradation in the lysosome. Dysfunction of autophagy has been implicated in many diseases including neurodegenerative diseases, cancer, and infectious diseases. Beta-propeller Protein-Associated Neurodegeneration (BPAN), an early onset neurodegenerative disease, is caused by mutations in WIPI4, a member of the WD repeat domain phosphoinositide-interacting family. This thesis identifies WIPI4 as a regulator of the closure of autophagosomes. Although many proteins have been found to indirectly regulate autophagosome closure, the exact mechanism of this process has remained unclear. This thesis explored the regulatory mechanism of GABARAP by WIPI4. GABARAP is a potential closure regulator and is also required for expansion and fusion steps of autophagy. I identified that WIPI4 regulates the stability and trafficking of GABARAP. Altogether, this thesis furthers the understanding of the mechanism of autophagosome closure.
Subjects/Keywords: autophagy; proteasome; neurodegeneration disease
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APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Zhu, Y. (2020). Studies on the autophagy gene WIPI4 and its interactor UBR5. (Doctoral Dissertation). University of Cambridge. Retrieved from https://www.repository.cam.ac.uk/handle/1810/300658
Chicago Manual of Style (16th Edition):
Zhu, Ye. “Studies on the autophagy gene WIPI4 and its interactor UBR5.” 2020. Doctoral Dissertation, University of Cambridge. Accessed March 04, 2021.
https://www.repository.cam.ac.uk/handle/1810/300658.
MLA Handbook (7th Edition):
Zhu, Ye. “Studies on the autophagy gene WIPI4 and its interactor UBR5.” 2020. Web. 04 Mar 2021.
Vancouver:
Zhu Y. Studies on the autophagy gene WIPI4 and its interactor UBR5. [Internet] [Doctoral dissertation]. University of Cambridge; 2020. [cited 2021 Mar 04].
Available from: https://www.repository.cam.ac.uk/handle/1810/300658.
Council of Science Editors:
Zhu Y. Studies on the autophagy gene WIPI4 and its interactor UBR5. [Doctoral Dissertation]. University of Cambridge; 2020. Available from: https://www.repository.cam.ac.uk/handle/1810/300658

University of Florida
15.
Kim, Mi-Jung.
Roles of Mitochondrial DNA Deletions, Point Mutations and Depletion in Age-Related Cochlear Neurodegeneration and Hearing Loss in Mice.
Degree: PhD, Medical Sciences - Molecular Cell Biology (IDP), 2018, University of Florida
URL: https://ufdc.ufl.edu/UFE0051774
Subjects/Keywords: cochlea; neurodegeneration
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❌
APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Kim, M. (2018). Roles of Mitochondrial DNA Deletions, Point Mutations and Depletion in Age-Related Cochlear Neurodegeneration and Hearing Loss in Mice. (Doctoral Dissertation). University of Florida. Retrieved from https://ufdc.ufl.edu/UFE0051774
Chicago Manual of Style (16th Edition):
Kim, Mi-Jung. “Roles of Mitochondrial DNA Deletions, Point Mutations and Depletion in Age-Related Cochlear Neurodegeneration and Hearing Loss in Mice.” 2018. Doctoral Dissertation, University of Florida. Accessed March 04, 2021.
https://ufdc.ufl.edu/UFE0051774.
MLA Handbook (7th Edition):
Kim, Mi-Jung. “Roles of Mitochondrial DNA Deletions, Point Mutations and Depletion in Age-Related Cochlear Neurodegeneration and Hearing Loss in Mice.” 2018. Web. 04 Mar 2021.
Vancouver:
Kim M. Roles of Mitochondrial DNA Deletions, Point Mutations and Depletion in Age-Related Cochlear Neurodegeneration and Hearing Loss in Mice. [Internet] [Doctoral dissertation]. University of Florida; 2018. [cited 2021 Mar 04].
Available from: https://ufdc.ufl.edu/UFE0051774.
Council of Science Editors:
Kim M. Roles of Mitochondrial DNA Deletions, Point Mutations and Depletion in Age-Related Cochlear Neurodegeneration and Hearing Loss in Mice. [Doctoral Dissertation]. University of Florida; 2018. Available from: https://ufdc.ufl.edu/UFE0051774

University of Missouri – Columbia
16.
Pinnegar, Abbie Jolene.
Investigating canine degenerative myelopathy as a disease model of amyotrophic lateral sclerosis for histopathological evidence of dysphagia.
Degree: 2012, University of Missouri – Columbia
URL: http://hdl.handle.net/10355/35437
► [ACCESS RESTRICTED TO THE UNIVERSITY OF MISSOURI AT REQUEST OF AUTHOR.] Unspecified swallowing impairment (dysphagia) was recently reported in dogs with degenerative myelopathy (DM), a…
(more)
▼ [ACCESS RESTRICTED TO THE UNIVERSITY OF MISSOURI AT REQUEST OF AUTHOR.] Unspecified swallowing impairment (dysphagia) was recently reported in dogs with degenerative myelopathy (DM), a proposed disease model of amyotrophic lateral sclerosis (ALS). The purpose of our study was to establish a clinicopathological correlation of dysphagia in canine DM. We investigated the brainstem nuclei involved in swallowing in DM and control dogs. Samples were procured from the College of Veterinary Medicine, University of Missouri. Subtle evidence of
neurodegeneration within each of the brainstem nuclei involved in swallowing was identified in DM samples using hematoxylin & eosin staining. Immunohistochemical methods are currently underway to substantiate this finding. Given that virtually all humans with ALS develop dysphagia, characterization of swallowing impairment is imperative to validate canine DM as a bona fide animal model of ALS. This line of research has the potential to benefit both people and dogs with dysphagia related to ALS and other diseases that cause dysphagia.
Advisors/Committee Members: Lever, Teresa E. (advisor).
Subjects/Keywords: dysphagia; brainstem nuclei; neurodegeneration
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APA ·
Chicago ·
MLA ·
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Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Pinnegar, A. J. (2012). Investigating canine degenerative myelopathy as a disease model of amyotrophic lateral sclerosis for histopathological evidence of dysphagia. (Thesis). University of Missouri – Columbia. Retrieved from http://hdl.handle.net/10355/35437
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Pinnegar, Abbie Jolene. “Investigating canine degenerative myelopathy as a disease model of amyotrophic lateral sclerosis for histopathological evidence of dysphagia.” 2012. Thesis, University of Missouri – Columbia. Accessed March 04, 2021.
http://hdl.handle.net/10355/35437.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Pinnegar, Abbie Jolene. “Investigating canine degenerative myelopathy as a disease model of amyotrophic lateral sclerosis for histopathological evidence of dysphagia.” 2012. Web. 04 Mar 2021.
Vancouver:
Pinnegar AJ. Investigating canine degenerative myelopathy as a disease model of amyotrophic lateral sclerosis for histopathological evidence of dysphagia. [Internet] [Thesis]. University of Missouri – Columbia; 2012. [cited 2021 Mar 04].
Available from: http://hdl.handle.net/10355/35437.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Pinnegar AJ. Investigating canine degenerative myelopathy as a disease model of amyotrophic lateral sclerosis for histopathological evidence of dysphagia. [Thesis]. University of Missouri – Columbia; 2012. Available from: http://hdl.handle.net/10355/35437
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

University of Minnesota
17.
Amar, Fatou.
Cellular And Molecular Mechanism Of Action Of The Amyloid-Beta Oligomer Abeta Star 56.
Degree: PhD, Neuroscience, 2016, University of Minnesota
URL: http://hdl.handle.net/11299/178973
► Alzheimer’s disease (AD) is a progressive neurodegenerative disorder, with asymptomatic and symptomatic phases. Hallmark lesions of AD include extracellular deposits of fibrillar amyloid-β (A β)…
(more)
▼ Alzheimer’s disease (AD) is a progressive neurodegenerative disorder, with asymptomatic and symptomatic phases. Hallmark lesions of AD include extracellular deposits of fibrillar amyloid-β (A β) and intracellular Neurofibrillary tangle formations (NFTs). However, recent evidence seems to support soluble oligomeric forms of amyloid proteins as bioactive species in AD. Amyloid-β oligomers (Aβo), such as Aβ*56, Aβ dimers and trimers have been demonstrated to be synaptotoxic species in AD. In particular, one of these oligomers, Aβ*56, was found to cause cognitive decline in the AD mouse model Tg2576, despite the absence of plaques and neuronal loss. In addition, cross-sectional studies suggest its possible involvement in the asymptomatic or preclinical phase of AD. However, it is currently unclear how this specific oligomer (Aβ*56) influences cellular and molecular processes to lead to cognitive deficits. My thesis focused on how Aβ*56 is able to disrupt cognition at the cellular and molecular level. First, we demonstrate that Aβ*56 forms a complex with NMDA receptors (NMDARs) resulting in an aberrant increase in intracellular calcium driven by synaptic NMDARs and the specific activation of the Ca2+/calmodulin dependent protein kinase CaMKIIα. Active CaMKIIα induces selective pathological changes in tau in vivo and in vitro, involving hyperphosphorylation and missorting. Importantly, other forms of endogenous Aβ oligomers do not appear to trigger these effects. Furthermore, other kinases such as GSK3, Cdk5 and fyn are not modulated by Aβ*56 in vitro. Interestingly, CaMKII phosphorylation is elevated in brain tissue of aged individuals, correlating with Aβ*56 abundance. These findings indicate that distinct Aβ oligomers activate specific neuronal signaling pathways in a highly selective manner in vitro. By extrapolation, these observations may have important consequences relative to our understanding of the different stages of AD.
Subjects/Keywords: Alzheimer's disease; molecular neuroscience; neurodegeneration
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APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
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APA (6th Edition):
Amar, F. (2016). Cellular And Molecular Mechanism Of Action Of The Amyloid-Beta Oligomer Abeta Star 56. (Doctoral Dissertation). University of Minnesota. Retrieved from http://hdl.handle.net/11299/178973
Chicago Manual of Style (16th Edition):
Amar, Fatou. “Cellular And Molecular Mechanism Of Action Of The Amyloid-Beta Oligomer Abeta Star 56.” 2016. Doctoral Dissertation, University of Minnesota. Accessed March 04, 2021.
http://hdl.handle.net/11299/178973.
MLA Handbook (7th Edition):
Amar, Fatou. “Cellular And Molecular Mechanism Of Action Of The Amyloid-Beta Oligomer Abeta Star 56.” 2016. Web. 04 Mar 2021.
Vancouver:
Amar F. Cellular And Molecular Mechanism Of Action Of The Amyloid-Beta Oligomer Abeta Star 56. [Internet] [Doctoral dissertation]. University of Minnesota; 2016. [cited 2021 Mar 04].
Available from: http://hdl.handle.net/11299/178973.
Council of Science Editors:
Amar F. Cellular And Molecular Mechanism Of Action Of The Amyloid-Beta Oligomer Abeta Star 56. [Doctoral Dissertation]. University of Minnesota; 2016. Available from: http://hdl.handle.net/11299/178973

University of Melbourne
18.
Price, Katherine Ann.
Investigating the cellular uptake, efflux and trafficking of metal complexes: implications for the therapy of neurodegeneration.
Degree: 2012, University of Melbourne
URL: http://hdl.handle.net/11343/37158
► Alzheimer’s disease (AD) and other neurodegenerative diseases such as Parkinson’s disease (PD) and amyotrophic lateral sclerosis (ALS) are characterized by altered biometal homeostasis. Low intracellular…
(more)
▼ Alzheimer’s disease (AD) and other neurodegenerative diseases such as Parkinson’s disease (PD) and amyotrophic lateral sclerosis (ALS) are characterized by altered biometal homeostasis. Low intracellular copper (Cu) levels have been observed in both AD and PD affected brain regions, while abnormal Cu metabolism by superoxide dismutase (SOD) may form the basis of some cases of ALS. Despite a surge in interest, the role of abnormal biometal balance and, in particular, homeostasis of Cu in these neurodegenerative diseases remains unclear. Growing evidence suggests that these changes in Cu homeostasis are an important early step in neurodegenerative processes. Restoring normal biometal metabolism may therefore offer a unique therapeutic opportunity. Supporting this, it has previously been shown that a bis(thiosemicarbazonato)copper(II) complex (CuII(btsc)) called CuII(gtsm) was capable of increasing intracellular Cu bio-availability and inhibited the accumulation of trimeric amyloid-beta (A) and phosphorylated tau in the brains of AD model mice and restored their cognitive function. Another CuII(btsc), CuII(atsm), has also produced positive effects in preliminary studies in multiple animal and cell models of PD and ALS. These Cu-complexes were initially investigated for use in cancer therapy and as imaging agents for hypoxic (low oxygen) tissues such as tumors, and the rationale for their application in neurodegenerative disease treatment was based on their ability to deliver metals into cells.
In the current project, mechanisms of uptake, intracellular distribution and efflux of two CuII(btsc) complexes in neuronal and glial-like cells were examined. The aim was to more thoroughly understand their cellular accumulation and trafficking profiles and potential use in therapy for neurodegeneration. A combination of inductively-coupled plasma mass spectrometry (ICP-MS), atomic absorption spectrometry (AAS), microscopic analyses and additional techniques were employed. This study found that no single mechanism was clearly responsible for the uptake of the CuII(btsc)s. Instead, a combination of passive diffusion and ATP-independent, facilitated uptake most likely mediated accumulation of the CuII(btsc)s in the U87MG glioblastoma and M17 neuroblastoma cell lines. Efflux of the CuII(btsc) complexes appeared to be dependent upon the ligand backbone of the complex and the data supported a rapid, ATP-dependent efflux process that was difficult to delineate temporally from uptake. To investigate the intracellular distribution of CuII(btsc) complexes, a fluorescent derivative of CuII(atsm) (termed CuIIL1) was used. Upon entry into cells, CuIIL1 localized to organelles of a lysosomal and possibly autophagic origin in the M17 cell line. This appeared to be associated with a robust down-regulation of BiP protein expression indicative of a possible role for the CuII(btsc)s in cellular ER stress.
Confocal microscopic studies were also performed…
Subjects/Keywords: biometals; cell metabolism; trafficking; neurodegeneration
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❌
APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Price, K. A. (2012). Investigating the cellular uptake, efflux and trafficking of metal complexes: implications for the therapy of neurodegeneration. (Doctoral Dissertation). University of Melbourne. Retrieved from http://hdl.handle.net/11343/37158
Chicago Manual of Style (16th Edition):
Price, Katherine Ann. “Investigating the cellular uptake, efflux and trafficking of metal complexes: implications for the therapy of neurodegeneration.” 2012. Doctoral Dissertation, University of Melbourne. Accessed March 04, 2021.
http://hdl.handle.net/11343/37158.
MLA Handbook (7th Edition):
Price, Katherine Ann. “Investigating the cellular uptake, efflux and trafficking of metal complexes: implications for the therapy of neurodegeneration.” 2012. Web. 04 Mar 2021.
Vancouver:
Price KA. Investigating the cellular uptake, efflux and trafficking of metal complexes: implications for the therapy of neurodegeneration. [Internet] [Doctoral dissertation]. University of Melbourne; 2012. [cited 2021 Mar 04].
Available from: http://hdl.handle.net/11343/37158.
Council of Science Editors:
Price KA. Investigating the cellular uptake, efflux and trafficking of metal complexes: implications for the therapy of neurodegeneration. [Doctoral Dissertation]. University of Melbourne; 2012. Available from: http://hdl.handle.net/11343/37158

University of Melbourne
19.
Harrington, Karra.
Undetected preclinical neurodegenerative disease in models of normal cognitive aging.
Degree: 2018, University of Melbourne
URL: http://hdl.handle.net/11343/219895
► With population aging, understanding cognitive changes that occur in late life is vital to support these increasing numbers of older adults to maintain their wellbeing…
(more)
▼ With population aging, understanding cognitive changes that occur in late life is vital to support these increasing numbers of older adults to maintain their wellbeing and independence. Furthermore, accurate estimates of age-related cognitive change will enable the differentiation of early stage neurodegenerative disease from normal aging. Current cognitive aging models describe a pattern of progressive decline in memory,executive function, and processing speed abilities, and retention of experience-based knowledge, with increasing age. However, given that many older adults show signs of neurodegenerative disease, despite not meeting clinical criteria for dementia, it is possible that cognitive aging studies may have over-estimated the nature and magnitude of age-related cognitive decline. The aim of this thesis was to determine the extent to which undetected preclinical neurodegenerative disease could influence models of cognitive aging. Age-related change in cognition was examined in cognitively normal healthy older adults who underwent repeated clinical and neuropsychological assessments, as well as biomarker assessment for neurodegenerative disease. The influence of progression to mild cognitive impairment (MCI) and dementia was also considered. Results indicated that estimates of age-related cognitive decline were inflated by undetected disease. This was also found when the data were reconceptualised as intelligence factors and was confirmed across two cohorts and utilizing a range of analytic methods. Notably, in the absence of disease, increasing age was associated with stability of performance in episodic and working memory, and an attenuated rate of decline in some processing speed and executive functions. Together these results indicate that current expectations about cognitive loss in aging are biased by unrecognized neurodegenerative disease.
Subjects/Keywords: ageing; neurodegeneration; cognition; preclinical Alzheimer
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❌
APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Harrington, K. (2018). Undetected preclinical neurodegenerative disease in models of normal cognitive aging. (Doctoral Dissertation). University of Melbourne. Retrieved from http://hdl.handle.net/11343/219895
Chicago Manual of Style (16th Edition):
Harrington, Karra. “Undetected preclinical neurodegenerative disease in models of normal cognitive aging.” 2018. Doctoral Dissertation, University of Melbourne. Accessed March 04, 2021.
http://hdl.handle.net/11343/219895.
MLA Handbook (7th Edition):
Harrington, Karra. “Undetected preclinical neurodegenerative disease in models of normal cognitive aging.” 2018. Web. 04 Mar 2021.
Vancouver:
Harrington K. Undetected preclinical neurodegenerative disease in models of normal cognitive aging. [Internet] [Doctoral dissertation]. University of Melbourne; 2018. [cited 2021 Mar 04].
Available from: http://hdl.handle.net/11343/219895.
Council of Science Editors:
Harrington K. Undetected preclinical neurodegenerative disease in models of normal cognitive aging. [Doctoral Dissertation]. University of Melbourne; 2018. Available from: http://hdl.handle.net/11343/219895

University of Cambridge
20.
Levy, Daniel Robert Siegfried.
Exploring the role of Leucine Rich Repeat Kinase 2 within the innate immune system.
Degree: PhD, 2018, University of Cambridge
URL: https://doi.org/10.17863/CAM.20803
;
https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.744573
► Leucine rich repeat kinase 2 (LRRK2) is a 286 kDa protein expressed in a variety of tissues and cell types, including neuronal tissue and innate…
(more)
▼ Leucine rich repeat kinase 2 (LRRK2) is a 286 kDa protein expressed in a variety of tissues and cell types, including neuronal tissue and innate immune cells. Mutations in LRRK2 have been linked to inflammatory diseases, most notably Crohn’s disease and Parkinson’s disease. Further to this, LRRK2 expression is induced by innate immune stimuli, and can be phosphorylated by Myd88 directed TLR signalling. Functional experiments were performed using macrophages from WT and LRRK2 knockout mice. Many phenotypes and interactions have been described for LRRK2 in a neuronal or in vitro context; therefore experiments in macrophages were specifically designed to investigate these phenotypes and interactions in an innate immune context. LRRK2 interacts with a range of small GTPase proteins called Rabs, which coordinate and carry out vesicular trafficking, including that of innate immune receptors. Further interactions have been shown with clathrin-mediated endocytic machinery and phagocytic machinery; including cytoskeletal components actin and tubulin. Accordingly, the role of LRRK2 in the expression, membrane localisation, and ligand-induced endocytosis of the innate immune receptors such as TLR4 were assayed. TLR4 plays an important role in immune responses to alpha-synuclein, an immunogenic protein aggregate that accumulates as part of Parkinson’s disease pathology, making it a particularly interesting target for this assay. No effect was shown for LRRK2 on TLR4 expression or receptor mediated endocytosis, so attention was focused upon LRRK2 cytoskeletal interactions. An unclear role of LRRK2 has been described in phagocytosis. Application of LRRK2 KO macrophages in a series of systematic phagocytosis assays was used to demonstrate and clarify that there is no role of LRRK2 in the phagocytosis of simple beads, opsonised material, or complex bacterial targets expressing a range of immunogenic molecules such as LPS. A genome wide approach was applied to further investigate the role of LRRK2 in TLR4 mediated signalling, as well as NOD2 mediated signalling. Comparison of LPS responses between WT and LRRK2 KO genotype macrophages identified a role of LRRK2 in modulating transcription of a range of chemokines and chemokine receptors. This indicates a specific role of LRRK2 in regulating chemotaxis in LPS stimulated cells. Knockout of LRRK2 resulted in a complete reversal of the regulation of the expression of EPAC1, a cAMP inducible protein working in parallel with a previously described LRRK2 interacting protein PKA. EPAC1 acts, at least in part, via Ca2+ signalling. Modulation of signalling through pathways such as Ca2+, Wnt and cAMP appear as a theme in results described in this transcriptomic experiment. A parallel metabolomic approach allowed analysis of ceramide levels in resting and innate immune stimulated macrophages. Ceramides are lipid molecules able to activate the NLRP3 inflammasome, as well as modulate alpha-synuclein pathology via ceramide metabolomic products. In contrast to results described in neuronal tissue,…
Subjects/Keywords: 616.8; immunology; Parkinson's disease; neurodegeneration
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❌
APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Levy, D. R. S. (2018). Exploring the role of Leucine Rich Repeat Kinase 2 within the innate immune system. (Doctoral Dissertation). University of Cambridge. Retrieved from https://doi.org/10.17863/CAM.20803 ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.744573
Chicago Manual of Style (16th Edition):
Levy, Daniel Robert Siegfried. “Exploring the role of Leucine Rich Repeat Kinase 2 within the innate immune system.” 2018. Doctoral Dissertation, University of Cambridge. Accessed March 04, 2021.
https://doi.org/10.17863/CAM.20803 ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.744573.
MLA Handbook (7th Edition):
Levy, Daniel Robert Siegfried. “Exploring the role of Leucine Rich Repeat Kinase 2 within the innate immune system.” 2018. Web. 04 Mar 2021.
Vancouver:
Levy DRS. Exploring the role of Leucine Rich Repeat Kinase 2 within the innate immune system. [Internet] [Doctoral dissertation]. University of Cambridge; 2018. [cited 2021 Mar 04].
Available from: https://doi.org/10.17863/CAM.20803 ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.744573.
Council of Science Editors:
Levy DRS. Exploring the role of Leucine Rich Repeat Kinase 2 within the innate immune system. [Doctoral Dissertation]. University of Cambridge; 2018. Available from: https://doi.org/10.17863/CAM.20803 ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.744573

University of Sydney
21.
Cross, Nathan.
Obstructive sleep apnoea in older adults: Predictors of cognitive decline and neurodegeneration
.
Degree: 2017, University of Sydney
URL: http://hdl.handle.net/2123/17763
► There is growing evidence that sleep disturbances share associations with neurodegeneration, and poor sleep is emerging as an independent risk factor for dementia. As a…
(more)
▼ There is growing evidence that sleep disturbances share associations with neurodegeneration, and poor sleep is emerging as an independent risk factor for dementia. As a common sleep disorder, obstructive sleep apnea (OSA) has been connected to compromised cognition, brain integrity and an increased risk for dementia. However, there is a need to clarify these relationships in older adults and understand the mechanisms underpinning the link between OSA and cognitive decline. The aims of this thesis were: 1) to characterise and quantitatively analyse the relationship between OSA and cognitive function in older adults, 2) to determine whether any changes in neural oscillations during sleep or brain grey matter thickness and volume, might be associated with OSA and related to makers of cognitive decline (e.g. memory) in a sample of older adults at-risk for dementia. At-risk adults were diagnosed as health-seeking older adults (>50 years) with subjective or objective cognitive impairment. Neural oscillations were recorded using electroencephalography and brain grey matter thickness and volume were measured using magnetic resonance imaging. These findings showed that the presence of OSA in at-risk older adults is related to a marked reduction in specific neural oscillations (sleep spindles), key aspects of sleep microarchitecture that are integrally linked with memory consolidation. Furthermore, OSA-related oxygen desaturation was associated with decreased cortical thickness in both the left and right temporal lobes, while sleep disturbance was related to increased cortical thickness in in frontal, central and occipital regions of the right cortex. This work has provided evidence that OSA is related to features which may contribute to early-stage neurodegeneration and cognitive decline, which are important in identifying critical periods for intervention. Given that effective treatment exists for OSA, efforts to increase OSA screening in older adults are now warranted.
Subjects/Keywords: sleep;
apnoea;
ageing;
neurodegeneration
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❌
APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Cross, N. (2017). Obstructive sleep apnoea in older adults: Predictors of cognitive decline and neurodegeneration
. (Thesis). University of Sydney. Retrieved from http://hdl.handle.net/2123/17763
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Cross, Nathan. “Obstructive sleep apnoea in older adults: Predictors of cognitive decline and neurodegeneration
.” 2017. Thesis, University of Sydney. Accessed March 04, 2021.
http://hdl.handle.net/2123/17763.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Cross, Nathan. “Obstructive sleep apnoea in older adults: Predictors of cognitive decline and neurodegeneration
.” 2017. Web. 04 Mar 2021.
Vancouver:
Cross N. Obstructive sleep apnoea in older adults: Predictors of cognitive decline and neurodegeneration
. [Internet] [Thesis]. University of Sydney; 2017. [cited 2021 Mar 04].
Available from: http://hdl.handle.net/2123/17763.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Cross N. Obstructive sleep apnoea in older adults: Predictors of cognitive decline and neurodegeneration
. [Thesis]. University of Sydney; 2017. Available from: http://hdl.handle.net/2123/17763
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

University of New South Wales
22.
Chiu, Alexander Simon Che-Kean.
A toxicological analysis of the cyanotoxin β-methylamino-L-alanine at multiple neural levels and identification of novel modes of activity.
Degree: Biotechnology & Biomolecular Sciences, 2013, University of New South Wales
URL: http://handle.unsw.edu.au/1959.4/52422
;
https://unsworks.unsw.edu.au/fapi/datastream/unsworks:11095/SOURCE01?view=true
► The cyanotoxin β-methylamino-L-alanine (BMAA) has long been associated with the elevated incidence of amyotrophic lateral sclerosis/Parkinsonism dementia complex (ALS/PDC). BMAA has been shown to be…
(more)
▼ The cyanotoxin β-methylamino-L-alanine (BMAA) has long been associated with the elevated incidence of amyotrophic lateral sclerosis/Parkinsonism dementia complex (ALS/PDC). BMAA has been shown to be produced across the cyanobacterial order and its detection has been reported in a variety of aquatic and terrestrial environments worldwide, suggesting that it is ubiquitous. Various in vivo studies on rats, mice, chicks, monkeys and zebrafish have shown that BMAA can cause neurodegenerative symptoms such as ataxia and convulsions, as well as disruption to neural development. Previous in vitro studies using mice, rats and leeches have shown that BMAA acts predominantly on motor neurons. Observed increases in the generation of reactive oxygen species (ROS) and Ca2+ influx, coupled with disruption to mitochondrial activity and general neuronal death, indicate that the main mode of activity is via excitotoxic mechanisms. Data presented here indicate that BMAA induces increased intracellular Ca2+ influx, DNA damage, mitochondrial activity, lactate dehydrogenase (LDH) release and generation of ROS in human neurons. The amelioration of LDH release in the presence of the N methyl-D-aspartate (NMDA) receptor antagonist MK801 indicates that the neurotoxic effects of BMAA are mediated via NMDA receptor activation. Immunocytochemical stains show that BMAA induces the expression of neuronal nitric oxide synthase (nNOS) and caspase-3 indicating that it can stimulate apoptosis in human neurons, presumably via activation of NMDA receptors. Rat olfactory ensheathing cells (OECs) were also challenged with exogenous BMAA resulting in elevated cell death. Significant increases in Ca2+ influx, enhanced production of ROS, and disruption to mitochondrial activity were observed in OECs. This is the first study investigating BMAA toxicity using pure glial cells. These findings align BMAA with all proposed mechanisms of degeneration in ALS, those being non-cell autonomous death, excitotoxicity and mitochondrial dysfunction. Additionally, novel genes and proteins have been identified that were differentially expressed in BMAA treated OECs. Some of the identified genes/proteins of interest have previously been linked to Alzheimer's disease. Other genes/proteins identified have reported functions in the regulation of mitochondrial activity and cell cycle and apoptosis. Cell cycle analysis of OECs treated with BMAA resulted in cell cycle arrest at the G2/M phase.
Advisors/Committee Members: Neilan, Brett, Biotechnology & Biomolecular Sciences, Faculty of Science, UNSW, Welch, Jeffrey, Biotechnology & Biomolecular Sciences, Faculty of Science, UNSW.
Subjects/Keywords: ALS/PDC; BMAA; Neurodegeneration; Cyanotoxin
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APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Chiu, A. S. C. (2013). A toxicological analysis of the cyanotoxin β-methylamino-L-alanine at multiple neural levels and identification of novel modes of activity. (Doctoral Dissertation). University of New South Wales. Retrieved from http://handle.unsw.edu.au/1959.4/52422 ; https://unsworks.unsw.edu.au/fapi/datastream/unsworks:11095/SOURCE01?view=true
Chicago Manual of Style (16th Edition):
Chiu, Alexander Simon Che-Kean. “A toxicological analysis of the cyanotoxin β-methylamino-L-alanine at multiple neural levels and identification of novel modes of activity.” 2013. Doctoral Dissertation, University of New South Wales. Accessed March 04, 2021.
http://handle.unsw.edu.au/1959.4/52422 ; https://unsworks.unsw.edu.au/fapi/datastream/unsworks:11095/SOURCE01?view=true.
MLA Handbook (7th Edition):
Chiu, Alexander Simon Che-Kean. “A toxicological analysis of the cyanotoxin β-methylamino-L-alanine at multiple neural levels and identification of novel modes of activity.” 2013. Web. 04 Mar 2021.
Vancouver:
Chiu ASC. A toxicological analysis of the cyanotoxin β-methylamino-L-alanine at multiple neural levels and identification of novel modes of activity. [Internet] [Doctoral dissertation]. University of New South Wales; 2013. [cited 2021 Mar 04].
Available from: http://handle.unsw.edu.au/1959.4/52422 ; https://unsworks.unsw.edu.au/fapi/datastream/unsworks:11095/SOURCE01?view=true.
Council of Science Editors:
Chiu ASC. A toxicological analysis of the cyanotoxin β-methylamino-L-alanine at multiple neural levels and identification of novel modes of activity. [Doctoral Dissertation]. University of New South Wales; 2013. Available from: http://handle.unsw.edu.au/1959.4/52422 ; https://unsworks.unsw.edu.au/fapi/datastream/unsworks:11095/SOURCE01?view=true

Texas State University – San Marcos
23.
Stavinoha, Rebecca C.
In Vivo Neuroprotective Effects of Cinnamon Bioactive Compounds in C. elegans and D. melanogaster.
Degree: MS, Human Nutrition, 2015, Texas State University – San Marcos
URL: https://digital.library.txstate.edu/handle/10877/8766
Subjects/Keywords: Cinnamon; Neurodegeneration
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APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
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APA (6th Edition):
Stavinoha, R. C. (2015). In Vivo Neuroprotective Effects of Cinnamon Bioactive Compounds in C. elegans and D. melanogaster. (Masters Thesis). Texas State University – San Marcos. Retrieved from https://digital.library.txstate.edu/handle/10877/8766
Chicago Manual of Style (16th Edition):
Stavinoha, Rebecca C. “In Vivo Neuroprotective Effects of Cinnamon Bioactive Compounds in C. elegans and D. melanogaster.” 2015. Masters Thesis, Texas State University – San Marcos. Accessed March 04, 2021.
https://digital.library.txstate.edu/handle/10877/8766.
MLA Handbook (7th Edition):
Stavinoha, Rebecca C. “In Vivo Neuroprotective Effects of Cinnamon Bioactive Compounds in C. elegans and D. melanogaster.” 2015. Web. 04 Mar 2021.
Vancouver:
Stavinoha RC. In Vivo Neuroprotective Effects of Cinnamon Bioactive Compounds in C. elegans and D. melanogaster. [Internet] [Masters thesis]. Texas State University – San Marcos; 2015. [cited 2021 Mar 04].
Available from: https://digital.library.txstate.edu/handle/10877/8766.
Council of Science Editors:
Stavinoha RC. In Vivo Neuroprotective Effects of Cinnamon Bioactive Compounds in C. elegans and D. melanogaster. [Masters Thesis]. Texas State University – San Marcos; 2015. Available from: https://digital.library.txstate.edu/handle/10877/8766

University of New South Wales
24.
Braidy, Nady.
NAD+ metabolism in neurodegeneration and aging.
Degree: Medical Sciences, 2011, University of New South Wales
URL: http://handle.unsw.edu.au/1959.4/51345
;
https://unsworks.unsw.edu.au/fapi/datastream/unsworks:10026/SOURCE02?view=true
► Elevated levels of several kynurenine pathway (KP) metabolites, e.g. quinolinic acid (QUIN), have been implicated in the aetiology of several neurodegenerative diseases such as Alzheimer‟s…
(more)
▼ Elevated levels of several kynurenine pathway (KP) metabolites, e.g. quinolinic acid (QUIN), have been implicated in the aetiology of several neurodegenerative diseases such as Alzheimer‟s disease (AD) and Multiple Sclerosis (MS). The end product of the KP is NAD+, an essential cofactor for energy metabolism. NAD+ also serves as the sole substrate for the DNA repair enzyme, poly(ADP-ribose) polymerase (PARP). More recently, NAD+ has been identified as an essential substrate for a new class of histone deacetylases known as SIRT1, which has been linked to longevity. Free radical mediated PARP activation and NAD+ depletion may contribute to brain aging and tissue damage in multiple brain disorders.Our results indicate a direct involvement of the KP in NAD+ synthesis in human brain cells, and that reduced intracellular NAD+ synthesis leads to reduced activity of NAD+ dependent histone deacetylase function. We show that the KP metabolite and NMDA receptor agonist, QUIN is a substrate of NAD+ synthesis in nanomolar concentrations in both astrocytes and neurons but is cytotoxic at higher amounts in both cell types. These results also show a clear neuroprotective effect of NMDA receptor antagonism and nitric oxide synthase inhibition against QUIN mediated neuronal and glial cytoxicity, strongly suggesting that QUIN-induced excitotoxicity in astrocytes and neurons is mediated by overactivation of the NMDA receptor. We also show that natural polyphenolic compounds can attenuate QUIN-mediated neurotoxicity by a number of mechanisms reported herein.We also provide evidence for the first time that tryptophan metabolism leading to NAD+ synthesis is unregulated in tissue obtained from aged female wistar rats. SIRT1 activity was also decreased and acetylated p53 increased in these same animals in response to an unregulated PARP-mediated NAD+ depletion. Consistent with these animal data we also found that human serum NAD+ levels are reduced in MS.
Advisors/Committee Members: Grant, Ross, Medical Sciences, Faculty of Medicine, UNSW, Guillemin, Gilles, Medical Sciences, Faculty of Medicine, UNSW.
Subjects/Keywords: NAD+; metabolism; neurodegeneration; aging
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APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Braidy, N. (2011). NAD+ metabolism in neurodegeneration and aging. (Doctoral Dissertation). University of New South Wales. Retrieved from http://handle.unsw.edu.au/1959.4/51345 ; https://unsworks.unsw.edu.au/fapi/datastream/unsworks:10026/SOURCE02?view=true
Chicago Manual of Style (16th Edition):
Braidy, Nady. “NAD+ metabolism in neurodegeneration and aging.” 2011. Doctoral Dissertation, University of New South Wales. Accessed March 04, 2021.
http://handle.unsw.edu.au/1959.4/51345 ; https://unsworks.unsw.edu.au/fapi/datastream/unsworks:10026/SOURCE02?view=true.
MLA Handbook (7th Edition):
Braidy, Nady. “NAD+ metabolism in neurodegeneration and aging.” 2011. Web. 04 Mar 2021.
Vancouver:
Braidy N. NAD+ metabolism in neurodegeneration and aging. [Internet] [Doctoral dissertation]. University of New South Wales; 2011. [cited 2021 Mar 04].
Available from: http://handle.unsw.edu.au/1959.4/51345 ; https://unsworks.unsw.edu.au/fapi/datastream/unsworks:10026/SOURCE02?view=true.
Council of Science Editors:
Braidy N. NAD+ metabolism in neurodegeneration and aging. [Doctoral Dissertation]. University of New South Wales; 2011. Available from: http://handle.unsw.edu.au/1959.4/51345 ; https://unsworks.unsw.edu.au/fapi/datastream/unsworks:10026/SOURCE02?view=true

Rhode Island College
25.
DeGrange, Roy W.
The Effect of Anesthesia on the Developing Brain.
Degree: MSN, 2019, Rhode Island College
URL: https://digitalcommons.ric.edu/etd/314
► Damage caused by administering general anesthetics to the developing brain in young children and pregnant mothers is of concern among practicing anesthesia providers. Studies…
(more)
▼ Damage caused by administering general anesthetics to the developing brain in young children and pregnant mothers is of concern among practicing anesthesia providers. Studies using young rodents and non-human primates have shown that animals are susceptible to neurodegeneration when exposed to high concentrations of general anesthesia. Randomized control trials using rodents as subjects used behavioral and histological experiments to determine the adverse effects of general anesthetics including the inhalation agents desflurane, isoflurane, and sevoflurane in addition to intravenous ketamine. The purpose of this systematic review was to examine the current literature to determine the effects these anesthetics pose on rodent subjects and how that translates into the human population. This systematic review was constructed using both PRISMA and ARRIVE as guidelines. A literature review was conducted and data was collected from each study. A cross-study analysis was created through data collected from each study by the author of this systematic review. The randomized control trials reviewed provide evidence that the types of inhalation and intravenous anesthesia agents studied can affect the developing brains of rodents. Anesthesia providers can use these results as a guide when administering anesthesia to infants, young children, and gravid mothers, however, more studies focusing on the long-term effects these agents have on children are warranted.
Subjects/Keywords:
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APA (6th Edition):
DeGrange, R. W. (2019). The Effect of Anesthesia on the Developing Brain. (Masters Thesis). Rhode Island College. Retrieved from https://digitalcommons.ric.edu/etd/314
Chicago Manual of Style (16th Edition):
DeGrange, Roy W. “The Effect of Anesthesia on the Developing Brain.” 2019. Masters Thesis, Rhode Island College. Accessed March 04, 2021.
https://digitalcommons.ric.edu/etd/314.
MLA Handbook (7th Edition):
DeGrange, Roy W. “The Effect of Anesthesia on the Developing Brain.” 2019. Web. 04 Mar 2021.
Vancouver:
DeGrange RW. The Effect of Anesthesia on the Developing Brain. [Internet] [Masters thesis]. Rhode Island College; 2019. [cited 2021 Mar 04].
Available from: https://digitalcommons.ric.edu/etd/314.
Council of Science Editors:
DeGrange RW. The Effect of Anesthesia on the Developing Brain. [Masters Thesis]. Rhode Island College; 2019. Available from: https://digitalcommons.ric.edu/etd/314

University of Cambridge
26.
Harris, Kate.
Understanding the role of dopamine in pathology and cognition in Huntington’s disease.
Degree: PhD, 2020, University of Cambridge
URL: https://www.repository.cam.ac.uk/handle/1810/315126
► Huntington’s disease is a genetic neurodegenerative disease caused by a CAG repeat expansion in the Huntingtin gene. Dysfunction of dopamine (DA) signalling is thought to…
(more)
▼ Huntington’s disease is a genetic neurodegenerative disease caused by a CAG repeat expansion in the Huntingtin gene. Dysfunction of dopamine (DA) signalling is thought to drive several of its clinical manifestations. DA receptors in frontostriatal pathways are lost early in the disease course – a possible compensatory response to increased dopaminergic activity, which is responsible for the hyperkinetic movement disorder of HD. DA signalling in frontostriatal pathways is also critical for cognitive processes such as executive function, and disruption of normal DA signalling may therefore contribute to cognitive impairments in HD. This thesis presents a number of clinical and laboratory studies, aiming to explore the importance of dopaminergic signalling in the pathogenesis of HD, and their contribution to the observed cognitive deficits. I first sought to explore the impact of DA modulation on cognitive function in HD. Firstly, using longitudinal data from the ENROLL-HD study, I have shown that the use of DA antagonists was associated with accelerated cognitive decline in early stage HD. I then performed an interventional study, in which cognitive function was characterised after administration of sulpiride (a D2 receptor-antagonist). Whilst sulpiride resulted in impaired executive function, there were improvements in other areas of dopamine-dependent cognition, such as reward-based decision-making and facial expression recognition. Taken together, these results suggest that DA signalling contributes to cognitive manifestations of HD. This relationship is complex, with D2 antagonism demonstrating opposing effects on different aspects of cognition. I next sought to characterise the anatomical and cellular basis for such deficits, as it appeared likely that these tasks involved other regions in addition to frontostriatal pathways. The hippocampus is known to play an important role in cognition, in particular in spatial memory, novelty encoding and reward processing. Given that DA has been shown to exert a modulatory influence on hippocampal neuronal and synaptic activity, I hypothesised that HD patients may also display hippocampal-related cognitive deficits. HD mice models have shown deficits in hippocampal synaptic plasticity, but little work has been done on hippocampal function in HD in humans. I therefore administered a hippocampal-dependent spatial memory task to HD gene carriers and found that early stage patients demonstrated impairments. The question as to whether the cause of such deficits had a possible DA basis led to the subsequent studies that I undertook. Evidence shows that glial cells play important roles in the pathogenesis of neurodegenerative diseases, and astrocytes have recently been shown to be involved in DA signalling. Specifically, DA activity at astrocyte DA receptors has neurotrophic and anti-inflammatory properties, and also increases intracellular Ca2+ transients in astrocytes, leading to the release of gliotransmitters which regulate synaptic plasticity. Astrocyte dysfunction in the…
Subjects/Keywords: Neuroscience; Neurodegeneration; Huntington's disease
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❌
APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Harris, K. (2020). Understanding the role of dopamine in pathology and cognition in Huntington’s disease. (Doctoral Dissertation). University of Cambridge. Retrieved from https://www.repository.cam.ac.uk/handle/1810/315126
Chicago Manual of Style (16th Edition):
Harris, Kate. “Understanding the role of dopamine in pathology and cognition in Huntington’s disease.” 2020. Doctoral Dissertation, University of Cambridge. Accessed March 04, 2021.
https://www.repository.cam.ac.uk/handle/1810/315126.
MLA Handbook (7th Edition):
Harris, Kate. “Understanding the role of dopamine in pathology and cognition in Huntington’s disease.” 2020. Web. 04 Mar 2021.
Vancouver:
Harris K. Understanding the role of dopamine in pathology and cognition in Huntington’s disease. [Internet] [Doctoral dissertation]. University of Cambridge; 2020. [cited 2021 Mar 04].
Available from: https://www.repository.cam.ac.uk/handle/1810/315126.
Council of Science Editors:
Harris K. Understanding the role of dopamine in pathology and cognition in Huntington’s disease. [Doctoral Dissertation]. University of Cambridge; 2020. Available from: https://www.repository.cam.ac.uk/handle/1810/315126

Kent State University
27.
Kumar, Varun.
Protein Kinase C Signaling in Neurodegeneration.
Degree: PhD, College of Arts and Sciences / School of Biomedical
Sciences, 2016, Kent State University
URL: http://rave.ohiolink.edu/etdc/view?acc_num=kent1455721051
► Global cerebral ischemia occurs due to cardiac arrest, which results in delayed neurodegeneration. Pharmacological agents such as Protein Kinase C epsilon (PKC epsilon) peptide activators…
(more)
▼ Global cerebral ischemia occurs due to cardiac arrest,
which results in delayed
neurodegeneration. Pharmacological agents
such as Protein Kinase C epsilon (PKC epsilon) peptide activators
when applied before ischemia are known to confer neuroprotection
against ischemia-induced cell death. However, the occurrence of
cardiac arrest or cerebral ischemia is unpredictable. Thus,
therapeutic targets that can be applied after ischemia have to be
unraveled. Moreover, the effect of PKC epsilon deletion after
global cerebral ischemia has not been studied yet. Therefore, we
have studied the effect of PKC epsilon deletion after global
cerebral ischemia. Using mouse model of global cerebral ischemia,
we found that hippocampal
neurodegeneration was significantly
reduced in knock-out (KO) mice compared with PKC epsilon wild-type
(WT) mice three days after ischemia. To determine the mechanisms
underlying the role of PKC epsilon in ischemia-induced
neurodegeneration, we have investigated the role of activating
transcription factor 2 (ATF2) and found that PKC epsilon regulates
the subcellular localization of ATF2 via Threonine 52 (Thr52)
phosphorylation and mediates apoptosis in hippocampal neurons. This
study will give insight into the role of PKC epsilon-ATF2 signaling
and other PKC isozymes in hippocampal neurons after global cerebral
ischemia. PKC delta, another member of novel PKC family, has been
implicated in stroke-reperfusion injury. To better study the role
of PKC delta in normal function and disease, we have developed an
ATP analog-specific PKC delta (AS-PKC delta) that is sensitive to
specific kinase inhibitors and can be used to identify PKC delta
substrates. To understand the mechanisms for specificity and
affinity of these analogs, we have created in silico WT and AS-PKC
delta homology models based on the crystal structure of Protein
Kinase C iota (PKC iota). N6-(benzyl)-ATP and ATP showed similar
positioning within the purine binding pocket of AS-PKC delta, while
N6-(benzyl)-ATP was displaced from the pocket of WT-PKC delta and
was unable to interact with the glycine-rich loop that is required
for phosphoryl-transfer. The adenine ring of 1NA-PP1 and 2MB-PP1
matched the adenine ring of ATP when docked in AS-PKC delta and
this interaction prevented the potential binding of ATP with
Lys-378, Glu-428, and Leu-430 residues. 1NA-PP1 failed to
effectively dock within WT-PKC delta. Moreover, other PP1 analogs
failed effectively to interact with either AS-PKC delta or WT-PKC
delta. These results provide a structural basis for the ability of
AS-PKC delta to efficiently and specifically utilize
N6-(benzyl)-ATP as a phosphate donor, and for its selective
inhibition by 1NA-PP1 and 2MB-PP1. Such homology modeling could
prove useful in designing molecules to target PKC delta and other
kinases to understand their function in cell signaling and to
identify unique substrates.
Advisors/Committee Members: Chou, Wen-Hai (Advisor).
Subjects/Keywords: Neurobiology; PKC, Neurodegeneration, ATF2
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APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Kumar, V. (2016). Protein Kinase C Signaling in Neurodegeneration. (Doctoral Dissertation). Kent State University. Retrieved from http://rave.ohiolink.edu/etdc/view?acc_num=kent1455721051
Chicago Manual of Style (16th Edition):
Kumar, Varun. “Protein Kinase C Signaling in Neurodegeneration.” 2016. Doctoral Dissertation, Kent State University. Accessed March 04, 2021.
http://rave.ohiolink.edu/etdc/view?acc_num=kent1455721051.
MLA Handbook (7th Edition):
Kumar, Varun. “Protein Kinase C Signaling in Neurodegeneration.” 2016. Web. 04 Mar 2021.
Vancouver:
Kumar V. Protein Kinase C Signaling in Neurodegeneration. [Internet] [Doctoral dissertation]. Kent State University; 2016. [cited 2021 Mar 04].
Available from: http://rave.ohiolink.edu/etdc/view?acc_num=kent1455721051.
Council of Science Editors:
Kumar V. Protein Kinase C Signaling in Neurodegeneration. [Doctoral Dissertation]. Kent State University; 2016. Available from: http://rave.ohiolink.edu/etdc/view?acc_num=kent1455721051

University of Cambridge
28.
Humoud, Ibrahim.
Investigating the potential of enhanced neuroprotection through unfolded protein response inhibition and autophagy induction in neurodegeneration.
Degree: PhD, 2019, University of Cambridge
URL: https://www.repository.cam.ac.uk/handle/1810/310338
► Neurodegenerative diseases pose an immense challenge to the population and health care worldwide. There is a growing need for therapeutic strategies to target these diseases.…
(more)
▼ Neurodegenerative diseases pose an immense challenge to the population and health care worldwide. There is a growing need for therapeutic strategies to target these diseases. Many neurodegenerative diseases are classified as protein misfolding diseases (PMDs). Despite their uniqueness, these PMDs share common pathways connected to their pathophysiology. Preclinical evidence demonstrates that these can be manipulated for new disease-modifying drug therapies. The unfolded protein response (UPR) and autophagy are two such pathways, whose dysregulation is detectable as pathological hallmarks in various neurodegenerative diseases. The modulation of both pathways individually is neuroprotective in multiple mouse models of neurodegenerative disease. Evidence from other fields of biomedical research showed the enormous potential benefit of combination therapy in various human diseases. Therefore, this project aimed at investigating the strategy of combination therapy in neurodegeneration by targeting more than one common pathway compared to targeting each one singly. Here fore, two distinct models of neurodegeneration, prion disease and the tauopathy model, rTg4510, were used. It was confirmed that both common pathways, the UPR and autophagy, are implicated in the disease progression. Furthermore, targeting of either pathway, genetically or pharmacologically, demonstrated profound neuroprotection in the hippocampus of both mouse models and extended survival of prion-diseased mice significantly. However, neither genetic nor pharmacological combination therapy showed additive benefit when given early in the disease. When starting genetic or pharmacological treatment in a later phase of disease progression, combination therapy caused an extension of lifespan in prion-diseased mice beyond the effects of monotherapy alone. These results show that the modulation of autophagy genetically and pharmacologically is neuroprotective in prion-diseased mice to a similar extent to PERK pathway modulation. The combinatorial approach did not increase lifespan over monotherapy either genetically or pharmacologically, except when used later in the disease. The reasons for this remain to be explored, but the potential of targeting several processes is an appealing potential strategy in neurodegeneration.
Subjects/Keywords: Unfolded Protein Response; Autophagy; Neurodegeneration
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❌
APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Humoud, I. (2019). Investigating the potential of enhanced neuroprotection through unfolded protein response inhibition and autophagy induction in neurodegeneration. (Doctoral Dissertation). University of Cambridge. Retrieved from https://www.repository.cam.ac.uk/handle/1810/310338
Chicago Manual of Style (16th Edition):
Humoud, Ibrahim. “Investigating the potential of enhanced neuroprotection through unfolded protein response inhibition and autophagy induction in neurodegeneration.” 2019. Doctoral Dissertation, University of Cambridge. Accessed March 04, 2021.
https://www.repository.cam.ac.uk/handle/1810/310338.
MLA Handbook (7th Edition):
Humoud, Ibrahim. “Investigating the potential of enhanced neuroprotection through unfolded protein response inhibition and autophagy induction in neurodegeneration.” 2019. Web. 04 Mar 2021.
Vancouver:
Humoud I. Investigating the potential of enhanced neuroprotection through unfolded protein response inhibition and autophagy induction in neurodegeneration. [Internet] [Doctoral dissertation]. University of Cambridge; 2019. [cited 2021 Mar 04].
Available from: https://www.repository.cam.ac.uk/handle/1810/310338.
Council of Science Editors:
Humoud I. Investigating the potential of enhanced neuroprotection through unfolded protein response inhibition and autophagy induction in neurodegeneration. [Doctoral Dissertation]. University of Cambridge; 2019. Available from: https://www.repository.cam.ac.uk/handle/1810/310338

University of Alberta
29.
Mercer, Robert Corrigan Curtis.
The Prion Protein: Modulation of Potassium Channels and a
Novel Mouse Model of a Disease-Causing Hydrophobic Domain Insertion
Mutation.
Degree: PhD, Department of Medicine, 2016, University of Alberta
URL: https://era.library.ualberta.ca/files/cmp48sc82v
► Prion diseases are invariably fatal neurodegenerative diseases of humans and other mammals. While they can manifest as sporadic, infectious or genetic etiologies, the central event…
(more)
▼ Prion diseases are invariably fatal neurodegenerative
diseases of humans and other mammals. While they can manifest as
sporadic, infectious or genetic etiologies, the central event in
prion disease is the structural conversion of the prion protein
(PrPC) to an alternative conformer PrPSc. PrP is a highly enigmatic
molecule with a wide range of proposed functions and disease
associated phenotypes. A molecular understanding of the
physiological function of PrP and the pathological characteristics
of PrPSc is essential to uncover the means by which these diseases
may be combatted. Herein, I describe two sets of analysis: i) the
consequences of the physiological interaction between PrP and a
potassium channel modulating protein, dipeptidyl
aminopeptidase-like protein 6 (DPP6) and ii) the characterization
of a novel mouse model of a genetic form of prion disease,
Gerstmann–Sträussler–Scheinker disease (GSS). i) PrP, in a DPP6
dependent manner, enhances the properties of Kv4.2 voltage gated
potassium channels such that there is an increase in peak
amplitude, a rightward shift of the voltage-dependent steady-state
inactivation curve, a slower inactivation, and a faster recovery
from steady-state inactivation. ii) A patient presenting with GSS
was found to harbor a novel insertion mutation of the hydrophobic
domain of PrP. We created transgenic mice expressing this allele
and present a biochemical and histopathological workup of these
animals. They recapitulate many of the features of GSS, in
particular a defining low molecular weight proteinase K resistant
fragment of the prion protein. Brain extracts of affected animals
can be used to accelerate disease in mice expressing the same
insertion allele but wild type mice are refractory to this
treatment.
Subjects/Keywords: Gerstmann-Sträussler-Schienker; Potassium Channel; Prion; Neurodegeneration
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❌
APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Mercer, R. C. C. (2016). The Prion Protein: Modulation of Potassium Channels and a
Novel Mouse Model of a Disease-Causing Hydrophobic Domain Insertion
Mutation. (Doctoral Dissertation). University of Alberta. Retrieved from https://era.library.ualberta.ca/files/cmp48sc82v
Chicago Manual of Style (16th Edition):
Mercer, Robert Corrigan Curtis. “The Prion Protein: Modulation of Potassium Channels and a
Novel Mouse Model of a Disease-Causing Hydrophobic Domain Insertion
Mutation.” 2016. Doctoral Dissertation, University of Alberta. Accessed March 04, 2021.
https://era.library.ualberta.ca/files/cmp48sc82v.
MLA Handbook (7th Edition):
Mercer, Robert Corrigan Curtis. “The Prion Protein: Modulation of Potassium Channels and a
Novel Mouse Model of a Disease-Causing Hydrophobic Domain Insertion
Mutation.” 2016. Web. 04 Mar 2021.
Vancouver:
Mercer RCC. The Prion Protein: Modulation of Potassium Channels and a
Novel Mouse Model of a Disease-Causing Hydrophobic Domain Insertion
Mutation. [Internet] [Doctoral dissertation]. University of Alberta; 2016. [cited 2021 Mar 04].
Available from: https://era.library.ualberta.ca/files/cmp48sc82v.
Council of Science Editors:
Mercer RCC. The Prion Protein: Modulation of Potassium Channels and a
Novel Mouse Model of a Disease-Causing Hydrophobic Domain Insertion
Mutation. [Doctoral Dissertation]. University of Alberta; 2016. Available from: https://era.library.ualberta.ca/files/cmp48sc82v

Vanderbilt University
30.
Gibson, Chelsea Lynn.
Neurodegeneration and Metabolomic Impact of Genetic Elimination of the Orphan Metallo Beta-Lactamase, SWIP-10/MBLAC1.
Degree: PhD, Neuroscience, 2018, Vanderbilt University
URL: http://hdl.handle.net/1803/11175
► Glutamate (Glu) signaling plays a critical role in regulating neural excitability, thus supporting many behaviors. Perturbed Glu homeostasis in the brain is implicated in multiple…
(more)
▼ Glutamate (Glu) signaling plays a critical role in regulating neural excitability, thus supporting many behaviors. Perturbed Glu homeostasis in the brain is implicated in multiple psychiatric and neurodegenerative disorders including Parkinson’s disease, where theories implicate excitotoxic Glu signaling in dopamine (DA) neuron degeneration. Microscopy studies demonstrate that mutation to a glial expressed gene in C. elegans, swip-10, induces premature and progressive DA neuron degeneration typified by dystrophic dendritic processes, as well as shrunken and/or missing cell soma. DA neuron degeneration in swip-10 mutants is rescued by glial-specific expression of WT swip-10, and genetic studies implicate Glu signaling, Ca2+-permeable Glu receptors, intracellular Ca2+ signaling, and apoptotic cell death in swip-10 DA
neurodegeneration. Like swip-10, the putative mammalian ortholog, Mblac1, encodes a protein containing a metallo beta-lactamase domain. To gain insight into the role of MBLAC1 in vivo, CRISPR/Cas9 methods were employed to generate a MBLAC1 knockout (KO) model. Using serum from MBLAC1 KO and WT mice, untargeted metabolomic analyses were performed to nominate metabolic pathways responsive to MBLAC1 loss. Findings point to taurine metabolism, primary bile acid biosynthesis, and linoleate metabolism as pathways sensitive to loss of MBLAC1. The swip-10/MBLAC1 KO models serve as platforms for the elucidation of mechanisms that enhance risk for neurodegenerative diseases and/or the identification of agents that can limit excitotoxicity.
Advisors/Committee Members: Randy Blakely (committee member), Bruce Carter (committee member), David Miller (committee member), John McLean (committee member), Eric Delpire (Committee Chair).
Subjects/Keywords: C. elegans; dopamine; glia; glutamate; excitotoxicity; neurodegeneration
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❌
APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Gibson, C. L. (2018). Neurodegeneration and Metabolomic Impact of Genetic Elimination of the Orphan Metallo Beta-Lactamase, SWIP-10/MBLAC1. (Doctoral Dissertation). Vanderbilt University. Retrieved from http://hdl.handle.net/1803/11175
Chicago Manual of Style (16th Edition):
Gibson, Chelsea Lynn. “Neurodegeneration and Metabolomic Impact of Genetic Elimination of the Orphan Metallo Beta-Lactamase, SWIP-10/MBLAC1.” 2018. Doctoral Dissertation, Vanderbilt University. Accessed March 04, 2021.
http://hdl.handle.net/1803/11175.
MLA Handbook (7th Edition):
Gibson, Chelsea Lynn. “Neurodegeneration and Metabolomic Impact of Genetic Elimination of the Orphan Metallo Beta-Lactamase, SWIP-10/MBLAC1.” 2018. Web. 04 Mar 2021.
Vancouver:
Gibson CL. Neurodegeneration and Metabolomic Impact of Genetic Elimination of the Orphan Metallo Beta-Lactamase, SWIP-10/MBLAC1. [Internet] [Doctoral dissertation]. Vanderbilt University; 2018. [cited 2021 Mar 04].
Available from: http://hdl.handle.net/1803/11175.
Council of Science Editors:
Gibson CL. Neurodegeneration and Metabolomic Impact of Genetic Elimination of the Orphan Metallo Beta-Lactamase, SWIP-10/MBLAC1. [Doctoral Dissertation]. Vanderbilt University; 2018. Available from: http://hdl.handle.net/1803/11175
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