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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 \u03b1-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 \u03b1-synuclein condensation and toxicity in yeast and dopaminergic neurodegeneration in\n                    <jats:italic>C. elegans<\/jats:italic>\n                    . 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.\n                  <\/jats:p>","DOI":"10.7554\/elife.57457","type":"journal-article","created":{"date-parts":[[2020,12,15]],"date-time":"2020-12-15T08:35:06Z","timestamp":1608021306000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.57457","source":"Crossref","is-referenced-by-count":28,"title":["Therapeutic genetic variation revealed in diverse Hsp104 homologs"],"prefix":"10.7554","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2441-899X","authenticated-orcid":true,"given":"Zachary M","family":"March","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Biophysics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, United States"},{"name":"Department of Biochemistry and Molecular Biophysics Graduate Group, Perelman School of Medicine at the University 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the University of Pennsylvania, Philadelphia, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edward","family":"Chuang","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Biophysics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, United States"},{"name":"Pharmacology Graduate Group, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edward","family":"Gomes","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Biophysics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Corey W","family":"Willicott","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, The University of Alabama, Tuscaloosa, United 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