Therapeutic genetic variation revealed in diverse Hsp104 homologs.

Autor:	March ZM; Department of Biochemistry and Biophysics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, United States.; Department of Biochemistry and Molecular Biophysics Graduate Group, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, United States., Sweeney K; Department of Genetics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, United States.; Cell and Molecular Biology Graduate Group, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, United States.; Center for Cellular and Molecular Therapeutics, Children's Hospital of Philadelphia, Philadelphia, United States., Kim H; Department of Biological Sciences, The University of Alabama, Tuscaloosa, United States., Yan X; Department of Biological Sciences, The University of Alabama, Tuscaloosa, United States., Castellano LM; Department of Biochemistry and Biophysics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, United States.; Pharmacology Graduate Group, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, United States., Jackrel ME; Department of Biochemistry and Biophysics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, United States., Lin J; Department of Biochemistry and Biophysics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, United States., Chuang E; Department of Biochemistry and Biophysics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, United States.; Pharmacology Graduate Group, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, United States., Gomes E; Department of Biochemistry and Biophysics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, United States., Willicott CW; Department of Biological Sciences, The University of Alabama, Tuscaloosa, United States., Michalska K; Structural Biology Center, X-ray Science Division, Argonne National Laboratory, Argonne, United States.; Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, United States., Jedrzejczak RP; Structural Biology Center, X-ray Science Division, Argonne National Laboratory, Argonne, United States., Joachimiak A; Structural Biology Center, X-ray Science Division, Argonne National Laboratory, Argonne, United States.; Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, United States., Caldwell KA; Department of Biological Sciences, The University of Alabama, Tuscaloosa, United States., Caldwell GA; Department of Biological Sciences, The University of Alabama, Tuscaloosa, United States., Shalem O; Department of Genetics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, United States.; Cell and Molecular Biology Graduate Group, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, United States.; Center for Cellular and Molecular Therapeutics, Children's Hospital of Philadelphia, Philadelphia, United States., Shorter J; Department of Biochemistry and Biophysics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, United States.; Department of Biochemistry and Molecular Biophysics Graduate Group, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, United States.; Cell and Molecular Biology Graduate Group, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, United States.; Pharmacology Graduate Group, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, United States.
Jazyk:	angličtina
Zdroj:	ELife [Elife] 2020 Dec 15; Vol. 9. Date of Electronic Publication: 2020 Dec 15.
DOI:	10.7554/eLife.57457
Abstrakt:	The AAA+ protein disaggregase, Hsp104, increases fitness under stress by reversing stress-induced protein aggregation. Natural Hsp104 variants might exist with enhanced, selective activity against neurodegenerative disease substrates. However, natural Hsp104 variation remains largely unexplored. Here, we screened a cross-kingdom collection of Hsp104 homologs in yeast proteotoxicity models. Prokaryotic ClpG reduced TDP-43, FUS, and α-synuclein toxicity, whereas prokaryotic ClpB and hyperactive variants were ineffective. We uncovered therapeutic genetic variation among eukaryotic Hsp104 homologs that specifically antagonized TDP-43 condensation and toxicity in yeast and TDP-43 aggregation in human cells. We also uncovered distinct eukaryotic Hsp104 homologs that selectively antagonized α-synuclein condensation and toxicity in yeast and dopaminergic neurodegeneration in C. elegans . Surprisingly, this therapeutic variation did not manifest as enhanced disaggregase activity, but rather as increased passive inhibition of aggregation of specific substrates. By exploring natural tuning of this passive Hsp104 activity, we elucidated enhanced, substrate-specific agents that counter proteotoxicity underlying neurodegeneration. Competing Interests: ZM, KS, HK, XY, LC, MJ, JL, EC, EG, CW, KM, RJ, AJ, KC, GC, OS No competing interests declared, JS JS is a consultant for Dewpoint Therapeutics and Maze Therapeutics. (© 2020, March et al.)
Databáze:	MEDLINE
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