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

• Author / Creator

  Deng, Xiaodan

• 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.

• Subjects / Keywords

  • ER stress
  • Neurodegeneration
  • Multiple Sclerosis
  • Mitochondrial dynamics

• Graduation date

  Fall 2014

• Type of Item

  Thesis

• Degree

  Master of Science

• DOI

  https://doi.org/10.7939/R37951

• License

  This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.