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Author
Title Brain lipids and cholesterol in neuropsychiatric disorders
URL
Publication Date
Degree PhD
Discipline/Department Department of Human Genetics
Degree Level doctoral
University/Publisher McGill University
Abstract

Neuropsychiatric disorders and suicidal behaviour represent major contributions to mortality in Canada. Among the many factors associated with psychiatric disorders and suicide, alterations in lipids and cholesterol have been demonstrated both peripherally and centrally, supporting their roles as mediating variables in the underlying neuropathology. Cholesterol (CHL) regulation is a complex and dynamic system, and while animal studies also support a mediating role of CHL on brain function, efforts to determine a biological association in humans have achieved only modest gains. While mechanisms governing cholesterol regulation are not entirely understood, cholesterol is well accepted to have important impacts on a variety of brain functions from neurotransmission to synaptic plasticity and neurodegeneration, with unique contributions from neurons, astrocytes, and oligodendrocytes. Given the extensive regulatory feedback mechanisms and the implications in neurological function, determining a biological basis for the association of cholesterol with neuropsychiatric disorders remains an important area of research. This research aimed to explore the neurobiological mechanism whereby alterations in CHL may relate to neuropsychiatric phenotypes. The results presented in chapter 3 suggest, while no clear differences were found in suicide completers with major depressive disorder, expression of several CHL related genes associate more strongly with white matter CHL levels compared to grey matter, suggesting a potential contribution of SORT1, LPL, and ABCA2, in the regulation of white matter CHL. The results of chapter 4 suggest altered phospholipid levels and expression of lysosomal acid lipase A gene in violent suicides in the prefrontal cortex, which would have important consequences for inhibitory neurotransmission. The results of chapter 4 suggest an increase in 24-hydroxycholesterol in the prefrontal cortex of suicide completers and this could have implications for synapse maintenance and loss in the neuropathology of suicide. In regards to CHL levels, however, little evidence in support of alterations in CNS CHL in neuropsychiatric disorders and suicidal behaviour was noted.

Les troubles neuropsychiatriques et les comportements suicidaires contribuent de façon importante au taux de mortalité au Canada. Parmi les facteurs associés aux troubles neuropsychiatriques, on retrouve des altérations lipidiques autant périphériques que centrales, ce qui supporte une implication lipidique dans les mécanismes neuropathologiques. Étant donné la complexité des mécanismes régissant le cholestérol, et malgré les études animales qui soutiennent un rôle fonctionnel dans le cerveau, les déterminants biologiques sous-jacents à une telle association chez les humains demeurent incertains. Alors que les mécanismes impliqués dans la régulation du cholestérol ne sont pas entièrement compris, on attribue au cholestérol un rôle important dans la régulation de plusieurs fonctions cérébrales telles que la neurotransmission, les modifications…

Subjects/Keywords Biology - Neuroscience
Contributors Gustavo Turecki (Supervisor1); Naguib Mechawar (Supervisor2)
Language en
Rights All items in [email protected] are protected by copyright with all rights reserved unless otherwise indicated.
Country of Publication ca
Format application/pdf
Record ID oai:digitool.library.mcgill.ca:116838
Other Identifiers TC-QMM-116838
Repository mcgill
Date Retrieved
Date Indexed 2019-01-09
Grantor McGill University

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…Trimethylchlorosilane Violent White matter 17 ACKNOWLEDGEMENTS The author would like to thank first and foremost Gustavo Turecki and Naguib Mechawar for their guidance, patience, and support. Many thanks to Cristiana Cruceanu for, in addition to technical assistance…

…Funding was graciously provided by the Fonds de Recherche en Sant du Qubec (FRSQ), the Department of Human Genetics, and McGill University. Finally, this work would not have been possible without the continued encouragement of family and…

…friends. 18 STATEMENT OF ORIGINALITY This thesis is the work of Erika Freemantle and has been completed in fulfilment of the requirements of the degree of Doctor of Philosophy in the Department of Human Genetics, Faculty of Medicine at McGill University

…The following elements of the thesis constitute original pieces of work: Chapter 2: Monogenic disorders of cholesterol biosynthesis in relation to central nervous system function. Erika Freemantle, Naguib Mechawar, Gustavo Turecki Chapter 3…

…Relationship between grey and white matter gene expression and cholesterol levels in prefrontal cortical brain tissue of suicide completers. Erika Freemantle, Cristiana Cruceanu, Naguib Mechawar, Gustavo Turecki Chapter 4: Cholesterol and phospholipids in…

…cortex and synaptosomes of suicide completers: relationship with endosomal lipid trafficking genes Erika Freemantle, Naguib Mechawar, Gustavo Turecki Chapter 5: Analysis of oxysterols and cholesterol in prefrontal cortex of suicide completers Erika…

…Freemantle, Gary Gang Chen, Cristiana Cruceanu, Naguib Mechawar, Gustavo Turecki 19 CONTRIBUTION OF AUTHORS Chapter 1: Introduction. Erika Freemantle was responsible for the research and text. Naguib Mechawar and Gustavo Turecki contributed to revision of…

…text. Chapter 2: Monogenic disorders of cholesterol biosynthesis in relation to central nervous system function. Erika Freemantle was responsible for the research and text. Naguib Mechawar and Gustavo Turecki contributed to revision of the manuscript…

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