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Hsp90 and its co‐chaperone Sti1 control TDP‐43 misfolding and toxicity
Author(s) -
Lin Lilian TsaiWei,
Razzaq Abdul,
Di Gregorio Sonja E.,
Hong Soojie,
Charles Brendan,
Lopes Marilene H.,
Beraldo Flavio,
Prado Vania F.,
Prado Marco A. M.,
Duennwald Martin L.
Publication year - 2021
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.202002645r
Subject(s) - hsp90 , chaperone (clinical) , toxicity , protein folding , amyotrophic lateral sclerosis , inclusion bodies , protein aggregation , microbiology and biotechnology , heat shock protein , co chaperone , neurodegeneration , biology , chemistry , biochemistry , medicine , disease , gene , organic chemistry , pathology , escherichia coli
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.