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Lipid pathways in Huntington’s disease
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- Author / Creator
- Morales Burbano, Luis Carlos
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Huntington’s disease (HD) is a monogenic neurodegenerative disorder characterized by progressive choreic movements, dystonia, motor incoordination, cognitive decline and behavioural changes. HD is caused by an abnormal increase in the number of CAG repeats in the exon 1 of the huntingtin (HTT) gene, leading to an expanded polyglutamine stretch in the HTT protein. Mutant huntingtin (muHTT) is prone to misfold into toxic conformations and to aggregate, impairing vesicular transport, mitochondrial metabolism, cell signalling and gene transcription, and leading to neuronal dysfunction and death in various brain regions.
Our laboratory and others have shown that two distinct lipid biosynthetic pathways, the mevalonate pathway and the pathway for the synthesis of gangliosides, are also impaired in HD, potentially contributing to disease pathogenesis.
The mevalonate pathway is responsible for the production of cholesterol and isoprenoids. Isoprenoids are used for the prenylation of small GTPases, a crucial post-translational modification that regulates small GTPases activity and a wide range of downstream cell processes, including vesicular traffic and autophagy. Several studies have investigated the synthesis of cholesterol in HD models, but whether impairment of the mevalonate pathway could also lead to defective protein prenylation was not known, and has been investigated in the first part of this thesis.
I showed that steady-state prenylation of various representative small GTPases is not affected in a wide range of cell and animal HD models, in spite of downregulation of the mevalonate pathway. However, levels of one of these small GTPases, RAB7, a protein involved in vesicular transport and selective autophagy, were significantly decreased across models of HD.
Together with cholesterol, gangliosides are another class of lipids that are highly enriched in the brain and are crucial for neuronal functions. Studies in our laboratory showed that gangliosides levels are decreased in HD models and that administration of one ganglioside in particular, GM1, has profound therapeutic effects in HD mouse models. The underlying mechanisms were in part, investigated in this thesis.
I demonstrated that GM1 decreases accumulation of protein aggregates in HD cells, as well in a second model of proteotoxic stress represented by pharmacological inhibition of the ubiquitin-proteasome system, thus alleviating cellular stress.
Surprisingly, the beneficial effects of GM1 were not mediated by an increase in autophagy, a cellular process known to degrade muHTT aggregates and to be modulated by gangliosides in other model systems. Instead, I showed that administration of GM1 promotes the secretion of muHTT, as well as components of the aggresome, within extracellular vesicles (EVs). These are membrane-delimited vesicles that form within the multivesicular bodies (MVB) or that bud from the plasma membrane, carrying a wide array of proteins and nucleic acids, including toxic misfolded proteins. These data suggest that the neuroprotective activity of GM1 in HD models might be mediated, at least partially, by the secretion of toxic muHTT towards the extracellular space, thus relieving intracellular proteotoxic load in susceptible neurons. -
- Graduation date
- Fall 2018
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- Type of Item
- Thesis
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- Degree
- Doctor of Philosophy
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- License
- Permission is hereby granted to the University of Alberta Libraries to reproduce single copies of this thesis and to lend or sell such copies for private, scholarly or scientific research purposes only. Where the thesis is converted to, or otherwise made available in digital form, the University of Alberta will advise potential users of the thesis of these terms. The author reserves all other publication and other rights in association with the copyright in the thesis and, except as herein before provided, neither the thesis nor any substantial portion thereof may be printed or otherwise reproduced in any material form whatsoever without the author's prior written permission.