Degree
Master of Science
Program
Pathology
Supervisor
Dr. Martin Duennwald
Abstract
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease associated with protein misfolding and protein aggregation. In particular, the TAR DNA-binding protein (TDP-43) is often found in the pathological inclusions in neurons of ALS patient brains and spinal cords. This phenomenon is known as TDP-43 proteinopathy, the mislocalization of TDP-43 from the cell nucleus and the formation of aggregates in the cytoplasm. Numerous mutations in the gene encoding TDP-43 have also been linked to familial cases of ALS (fALS) and cause TDP-43 proteinopathy. This study attempts to decipher how the molecular chaperone Hsp90 and its co-chaperones, Aha1, Sti1, and Cdc37, modulate TDP-43 aggregation, mislocalization, and toxicity using a yeast model and cultured mammalian cells. We propose that Hsp90 stabilizes aberrant forms of TDP-43 and the inhibition of Hsp90 through moderate overexpression of Sti1 is able to rescue TDP-43 toxicity by modifying cytoplasmic TDP-43 aggregates.
Recommended Citation
Lin, Lilian T., "Hsp90 and its Co-chaperones Modify TDP-43 Localization, Aggregation, and Toxicity" (2017). Electronic Thesis and Dissertation Repository. 4434.
https://ir.lib.uwo.ca/etd/4434