AI Article Synopsis
- Protein misfolding is a key aspect of many neurodegenerative diseases, with TDP-43 misfolding being particularly relevant to ALS.
- Molecular chaperones like Hsp90 and its co-chaperone Sti1 can influence how TDP-43 misfolds and its associated toxicity within cells.
- The study highlights a crucial connection between Hsp90, Sti1, and TDP-43 misfolding, suggesting that disruptions in Hsp90 function heighten TDP-43 toxicity.
Article 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.
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| http://dx.doi.org/10.1096/fj.202002645R | DOI Listing |
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