RT Journal Article
SR Electronic
T1 Therapeutic genetic variation revealed in diverse Hsp104 homologs
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.03.25.008748
DO 10.1101/2020.03.25.008748
A1 Zachary M. March
A1 Katelyn Sweeney
A1 Hanna Kim
A1 Xiaohui Yan
A1 Laura M. Castellano
A1 Meredith E. Jackrel
A1 Edward Chuang
A1 Edward Gomes
A1 Karolina Michalska
A1 Robert Jedrzejczak
A1 Andrzej Joachimiak
A1 Kim A. Caldwell
A1 Guy A. Caldwell
A1 Ophir Shalem
A1 James Shorter
YR 2020
UL http://biorxiv.org/content/early/2020/03/26/2020.03.25.008748.abstract
AB The AAA+ protein disaggregase, Hsp104, increases fitness under stress by reversing stress-induced protein aggregation. We have engineered potentiated Hsp104 variants to antagonize proteotoxic misfolding linked to human neurodegenerative diseases. However, these Hsp104 variants can exhibit off-target toxicity, which may limit their therapeutic utility. Hsp104 is conserved among all nonmetazoan eukaryotes, which raises the possibility that natural variants might exist with enhanced, selective activity against neurodegenerative disease substrates. To assess this possibility, we screened a cross-kingdom collection of Hsp104 homologs in several yeast proteotoxicity models. We uncovered therapeutic genetic variation among several Hsp104 homologs that specifically antagonize TDP-43 or α-synuclein condensate formation and toxicity in yeast, human cells, and C. elegans. Surprisingly, this variation manifested as increased passive chaperone activity, distinct from disaggregase activity, which neutralizes proteotoxicity of specific substrates. Thus, by exploring natural tuning of passive chaperone activity we elucidated enhanced, substrate-specific agents to counter proteotoxicity underlying neurodegenerative disease.