Electronic Thesis and Dissertation Repository

Degree

Master of Science

Program

Pathology

Supervisor

Dr. Michael J. Strong

Abstract

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease for which the pathological mechanism is heterogeneous and a cure has been elusive. Recent developments have linked specific proteins found in pathological neuronal cytoplasmic inclusions (NCIs) of ALS motor neurons to familial variants of the disease. These proteins, including TAR DNA-binding protein of 43 kDa (TDP-43), fused in sarcoma/translocated in liposarcoma (FUS), and Rho guanine nucleotide exchange factor (RGNEF) share the common characteristic of being RNA-binding proteins that colocalize within NCIs. RGNEF is unique however in also possessing RhoA activation capacity, suggesting a role in the cell stress response. My thesis confirms this role, and I also observed that the domain responsible for RhoA activation is not critical for RGNEF’s protective effects. Altogether, my work further supports the hypothesis of a pathological mechanism of dysfunctional stress response in ALS motor neurons where cytoprotective proteins are sequestered in NCIs, leading to neurodegeneration.


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