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l o single residues in helix 1, 2, or 3 of the middle domain oligomers (DeSantis et al., 2012; Lo Bianco et al., 2008; Newby and Lindquist, 2013). Hsp104 also reactivates proteins fromProtein misfolding underpins several fatal neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS) and Par-kinson’s disease (PD) (Cushman et al., 2010). In PD, a-synuclein human neurodegenerative disease proteins, which Hsp104 never ordinarily encounters, and some substrates are refractory to Hsp104 (DeSantis et al., 2012; Lo Bianco et al., 2008).(a-syn) forms highly toxic prefibrillar oligomers and amyloid fibrils that accumulate in cytoplasmic Lewy bodies (Cushman et al., A key but elusive goal is to engineer or evolve optimized chaperones against neurodegenerative disease substrates toor the small domain of nucleotide-binding domain 1. Potentiated Hsp104 variants enhance aggregate dissolution, restore proper protein localization, sup-press proteotoxicity, and in a C. elegans PD model attenuate dopaminergic neurodegeneration. Poten-tiating mutations reconfigure how Hsp104 subunits collaborate, desensitize Hsp104 to inhibition, obviate any requirement for Hsp70, and enhance ATPase, translocation, and unfoldase activity. Our work es-tablishes that disease-associated aggregates and amyloid are tractable targets and that enhanced dis-aggregases can restore proteostasis and mitigate neurodegeneration