Electronic Thesis and Dissertation Repository


Master of Science




Prado, Marco A.M.

2nd Supervisor

Beraldo, Flavio H.


3rd Supervisor

Prado, Vania F.



A common hallmark of neurodegenerative disorders is the abnormal aggregation of misfolded proteins. Aggregates of phosphorylated TAR-DNA-binding protein-43 (TDP-43) are found in multiple neurodegenerative disorders. The molecular chaperones Hsp70 and Hsp90 have been shown to be key modulators of TDP-43 phosphorylation and expression, however the mechanisms behind how this interaction occur are unclear. Stress-Inducible PhosphoProtein 1 (STIP1) is a critical co-chaperone linking Hsp90 to Hsp70 to modulate chaperone client stability. In this study, we evaluated the potential role of STIP1 in TDP-43 stability and cellular toxicity. We demonstrated that STIP1 interacts with TDP-43 and the deletion of STIP1 leads to decreased TDP-43 protein expression in SN56 cells. In contrast, partial reduction of STIP1 in mice led to an increase in TDP-43 levels. Additionally, the deletion of STIP1 increased TDP-43 cytotoxicity in SN56 cells, whereas TDP-43 toxicity could be ameliorated by overexpressing STIP1 suggesting that STIP1 modulates TDP-43 toxicity and proteinopathy.

Available for download on Sunday, July 12, 2020