Hsp90 and its co-chaperone Sti1 control TDP-43 misfolding and toxicity

Author(s)

Lin, Lilian Tsai-Wei ^[1] ; Razzaq, Abdul ^[2] ; Di Gregorio, Sonja E. ^[1] ; Hong, Soojie ^[1] ; Charles, Brendan ^[1] ; Lopes, Marilene H. ^{[3, 4, 2]} ; Beraldo, Flavio ^{[2, 5]} ; Prado, Vania F. ^{[4, 2, 5]} ; Prado, Marco A. M. ^{[4, 2, 5]} ; Duennwald, Martin L. ^{[1, 4]}

Affiliation

^[1] Univ Western Ontario, Schulich Sch Med & Dent, Dept Pathol & Lab Med, London, ON - Canada

^[2] Univ Western Ontario, Schulich Sch Med & Dent, Robarts Res Inst, London, ON - Canada

^[3] Univ Sao Paulo, Inst Biomed Sci, Dept Cell & Dev Biol, Sao Paulo - Brazil

^[4] Univ Western Ontario, Schulich Sch Med & Dent, Dept Anat & Cell Biol, MSB 414, 1151 Richmond St, London, ON N6A 5C1 - Canada

^[5] Univ Western Ontario, Schulich Sch Med & Dent, Dept Physiol & Pharmacol, London, ON - Canada

• Document type: Journal article
• Source: FASEB JOURNAL; v. 35, n. 5 MAY 2021.
• Web of Science Citations: 0

Abstract

Protein misfolding is a central feature of most neurodegenerative diseases. Molecular chaperones can modulate the toxicity associated with protein misfolding, but it remains elusive which molecular chaperones and co-chaperones interact with specific misfolded proteins. TDP-43 misfolding and inclusion formation are a hallmark of amyotrophic lateral sclerosis (ALS) and other neurodegenerative diseases. Using yeast and mammalian neuronal cells we find that Hsp90 and its co-chaperone Sti1 have the capacity to alter TDP-43 misfolding, inclusion formation, aggregation, and cellular toxicity. Our data also demonstrate that impaired Hsp90 function sensitizes cells to TDP-43 toxicity and that Sti1 specifically interacts with and strongly modulates TDP-43 toxicity in a dose-dependent manner. Our study thus uncovers a previously unrecognized tie between Hsp90, Sti1, TDP-43 misfolding, and cellular toxicity. (AU)

• FAPESP's process: 19/00341-9 - Regulation of proteostasis in pluripotent stem cells by the co-chaperone STIP1
• Grantee: Marilene Hohmuth Lopes
• Support Opportunities: Regular Research Grants
• FAPESP's process: 16/00440-9 - Impact of co-chaperone STIP1 expression in the pluripotency acquision induced by Oct4 in murine fibroblasts
• Grantee: Marilene Hohmuth Lopes
• Support Opportunities: Scholarships abroad - Research