Summary There are no therapies that reverse the proteotoxic misfolding events that underpin fatal neurodegenerative diseases including amyotrophic lateral sclerosis (ALS) and Parkinson disease (PD). Hsp104, a conserved hexameric AAA+ protein from yeast, solubilizes disordered aggregates and amyloid, but has no metazoan homologue and only limited activity against human neurodegenerative disease proteins. Here, we reprogram Hsp104 to rescue TDP-43, FUS, and α-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 Hsp 104 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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Three studies tested the claim that H.M. exhibits a "pure memory deficit" that has left his ability to comprehend language unimpaired relative to memory-normal controls. In Study 1, H.M. and memory-normal controls of comparable intelligence, education, and age indicated whether sentences were ambiguous or unambiguous, and H. M. detected ambiguities significantly less often than controls. In Study 2, participants identified the two meanings of visually presented sentences that they knew were ambiguous, and relative to controls, H.M. rarely discovered the ambiguities without help and had difficulty understanding the first meanings, experimenter requests, and his own output. Study 3 replicated these results and showed that they were not due to brain damage per se or to cohort effects: Unlike H.M., a patient with bilateral frontal lobe damage detected the ambiguities as readily as young and same-cohort older controls. These results bear on two general classes of theories in use within a wide range of neurosciences and cognitive sciences: The data favor "distributed-memory theories" that ascribe H.M.'s deficit to semantic-level binding processes that are inherent to both language comprehension and memory, over "stages-of-processing theories," where H.M.'s defective storage processes have no effect on language comprehension.

The LINC complex component SUN2 contributes to the mechanical integrity of intercellular adhesions between mammalian epidermal keratinocytes.