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

Author:

Lin Lilian Tsai-WeiORCID,Razzaq Abdul,Di Gregorio Sonja E.,Hong SoojieORCID,Charles Brendan,Lopes Marilene H.ORCID,Beraldo Flavio,Prado Vania F.ORCID,Prado Marco A.M.ORCID,Duennwald Martin L.ORCID

Abstract

AbstractProtein 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 is a hallmark of amyotrophic lateral sclerosis (ALS) and other neurodegenerative diseases. Using yeast and mammalian neuronal cells we find that Hsp90 and its co-chaperones have a strong 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. We further show that the co-chaperone Sti1 specifically interacts with and modulates TDP-43 toxicity in a dose-dependent manner. Our study thus uncovers a previously unrecognized tie between Hsp90, Sti1, TDP-43 misfolding, and its cellular toxicity.

Publisher

Cold Spring Harbor Laboratory

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