Biological Sciences Division
Published December 15, 2020 | Version v1
Journal article Open

Therapeutic genetic variation revealed in diverse Hsp104 homologs

Creators

  • 1. University of Pennsylvania
  • 2. University of Alabama
  • 3. University of Chicago
  • 4. Argonne National Laboratory

Description

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 a-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 a-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.

Data availability

All data generated or analysed during this study are included in the manuscript.

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Additional details

Identifiers

DOI
10.7554/eLife.57457
Other
oai:uchicago.tind.io:9977

Funding

National Institutes of Health
R01GM099836
Muscular Dystrophy Association
ALS Association
Life Extension Foundation
Linda Montague Pechenik
Johns Hopkins University
Target ALS
National Science Foundation
DGE-0822
Alzheimer's Association
Research Fellowship
Warren Alpert Foundation
Distinguished Scholars Fellowship
Blavatnik Family Foundation
National Institutes of Health
T32GM071399
National Institutes of Health
F31NS101807
National Institutes of Health
T32GM008076

UChicago Information

Division(s)
Biological Sciences Division
Department(s)
Biochemistry and Molecular Biology