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

Autor: Lin LT; Department of Pathology and Laboratory Medicine, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada., Razzaq A; Robarts Research Institute, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada., Di Gregorio SE; Department of Pathology and Laboratory Medicine, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada., Hong S; Department of Pathology and Laboratory Medicine, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada., Charles B; Department of Pathology and Laboratory Medicine, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada., Lopes MH; Robarts Research Institute, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada.; Department of Anatomy & Cell Biology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada.; Department of Cell and Developmental Biology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil., Beraldo F; Robarts Research Institute, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada.; Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada., Prado VF; Robarts Research Institute, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada.; Department of Anatomy & Cell Biology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada.; Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada., Prado MAM; Robarts Research Institute, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada.; Department of Anatomy & Cell Biology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada.; Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada., Duennwald ML; Department of Pathology and Laboratory Medicine, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada.; Department of Anatomy & Cell Biology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada.
Jazyk: angličtina
Zdroj: FASEB journal : official publication of the Federation of American Societies for Experimental Biology [FASEB J] 2021 May; Vol. 35 (5), pp. e21594.
DOI: 10.1096/fj.202002645R
Abstrakt: 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.
(© 2021 Federation of American Societies for Experimental Biology.)
Databáze: MEDLINE
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