Hsp90 and its co-chaperone Sti1 control TDP-43 misfolding and toxicity.
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.
Mesh Terms:
Animals, Apoptosis, Binding Sites, DNA-Binding Proteins, Female, HSP90 Heat-Shock Proteins, HeLa Cells, Heat-Shock Proteins, Humans, Inclusion Bodies, Mice, Mice, Inbred C57BL, Mice, Knockout, Neurons, Protein Folding, Saccharomyces cerevisiae, TDP-43 Proteinopathies
Animals, Apoptosis, Binding Sites, DNA-Binding Proteins, Female, HSP90 Heat-Shock Proteins, HeLa Cells, Heat-Shock Proteins, Humans, Inclusion Bodies, Mice, Mice, Inbred C57BL, Mice, Knockout, Neurons, Protein Folding, Saccharomyces cerevisiae, TDP-43 Proteinopathies
FASEB J
Date: Dec. 01, 2020
PubMed ID: 33908654
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