Abstract Huntington’s disease (HD) is an autosomal dominant neurodegenerative disease with a well-characterized genetic etiology of a CAG expansion mutation in the huntingtin (HTT) gene, yet it remains without a cure. The hallmark of HD is the accumulation of intraneuronal aggregates of mutant HTT protein and polyglutamine (polyQ)-containing fragments, which cause impaired proteostasis and is an important HD therapeutic target. Aggregate-prone protein clearance primarily occurs through the autophagy-lysosome pathway and the ubiquitin-proteasome system, both of which can be modulated by deubiquitinating enzymes (DUBs). This study investigates the role of the DUB ubiquitin C-terminal hydrolase L3 (UCHL3) in modulating polyQ-mediated aggregation and toxicity. UCHL3 has previously been identified as a potential therapeutic target in cancer. We utilize HD models, including primary mouse neurons, patient fibroblasts, and patient-derived medium spiny neurons (MSN), which are the most vulnerable to HTT polyQ toxicity. Genetic lowering of UCHL3 decreased polyQ aggregates and increased autophagosome-lysosome fusion events. This was accompanied by STAT3 induction, which protects against neuronal proteotoxic stress. Furthermore, treatment with a small-molecule inhibitor of UCHL3 recapitulated the effects of UCHL3 lowering and attenuated pathological markers in HD MSN. These results provide a foundation for further exploration of UCHL3 inhibitors in the context of HD and underscore the biological connection between cancer and neurodegeneration for drug repurposing strategies.
Ishtayeh et al. (Fri,) studied this question.