Journal
CELL
Volume 156, Issue 1-2, Pages 170-182Publisher
CELL PRESS
DOI: 10.1016/j.cell.2013.11.047
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Funding
- American Heart Association postdoctoral fellowship
- NIH training grant [T32GM071339]
- NRSA predoctoral fellowship [F31NS079009]
- SF graduate research fellowship [DGE-0822]
- NSF CAREER Award [0845020]
- NIH [R15NS075684, R21NS067354, R21HD074510, R01GM099836]
- NIH Director's New Innovator Award [DP2OD002177]
- Muscular Dystrophy Association Research Award [MDA277268]
- Packard Center for ALS Research at Johns Hopkins University
- Target ALS
- Ellison Medical Foundation New Scholar in Aging Award
- Division Of Integrative Organismal Systems
- Direct For Biological Sciences [0845020] Funding Source: National Science Foundation
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There are no therapies that reverse the proteotoxic misfolding events that underpin fatal neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and Parkinson's disease (PD). Hsp104, a conserved hexameric AAA+ protein from yeast, solubilizes disordered aggregates and amyloid but has no metazoan homolog and only limited activity against human neurodegenerative disease proteins. Here, we reprogram Hsp104 to rescue TDP-43, FUS, and alpha-synuclein proteotoxicity by mutating single residues in helix 1, 2, or 3 of the middle domain or the small domain of nucleotide-binding domain 1. Potentiated Hsp104 variants enhance aggregate dissolution, restore proper protein localization, suppress proteotoxicity, and in a C. elegans PD model attenuate dopaminergic neurodegeneration. Potentiating mutations reconfigure how Hsp104 subunits collaborate, desensitize Hsp104 to inhibition, obviate any requirement for Hsp70, and enhance ATPase, translocation, and unfoldase activity. Our work establishes that disease-associated aggregates and amyloid are tractable targets and that enhanced disaggregases can restore proteostasis and mitigate neurodegeneration.
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