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Permanent link (DOI): https://doi.org/10.7939/R37951

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The Role of Mitochondrial Dynamics on Neurodegenerative Processes of Multiple Sclerosis in Respose to Inflammation and Endoplasmic Reticulum Stress Open Access

Descriptions

Other title
Subject/Keyword
ER stress
Mitochondrial dynamics
Multiple Sclerosis
Neurodegeneration
Type of item
Thesis
Degree grantor
University of Alberta
Author or creator
Deng, Xiaodan
Supervisor and department
Fabrizio, Giuliani (Medicine)
Examining committee member and department
David, Westaway (Medicine)
Thomas, Simmen (Cell Biology)
Simon, Gosgnach (Physiology)
Department
Centre for Neuroscience
Specialization

Date accepted
2014-09-23T12:00:16Z
Graduation date
2014-11
Degree
Master of Science
Degree level
Master's
Abstract
Biopsies and post-mortem tissue of patients with multiple sclerosis (MS) as well as inflammatory demyelinating animal models show that endoplasmic reticulum (ER) stress is a hallmark of the progression of these pathologies. Moreover, MS biopsies and animal models of neuroinflammatory diseases have detected axonal damage associated with mitochondria fragmentation and impaired distribution as an early event in absence of demyelination. It is thought that a combination of these phenomena makes cells more susceptible to inflammatory–mediated neurodegeneration and subsequent progression of the disease. Recent studies have demonstrated that Rab32, a small GTPase in the Ras protein family, plays a role in regulating mitochondrial mobility and ER stress induced apoptosis. Liang et al. showed that Rab32 expression sharply increases in response to acute brain inflammation, but subsequently drops. Based on the finding that activation of Rab32 induces ER stress related apoptosis and facilitates mitochondrial fragmentation via activation of dynamin-related protein 1 (Drp1), we hypothesize that Rab32 could play a role in altering the axonal mitochondrial distribution and inducing neurodegeneration in MS. In this study, we probed and measured the levels of Rab32 protein and functional related proteins Rab38 and Rab7L1, ER stress and apoptosis related proteins in acute as well as chronic lesions and normal-appearing white matter (NAWM) of inflamed MS brain tissues by Western blot and immunohistochemistry. Indeed, we found that high levels of Rab32 coincide with ER stress-associated apoptosis in acute lesions and its activation leads to shorter neurites with fragmented mitochondria in human neurons. Moreover, abnormal expression and activity of Rab32 accelerates apoptosis of human neurons, suggesting a role for Rab32 in neurodegenerative progression of MS.
Language
English
DOI
doi:10.7939/R37951
Rights
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.
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