Targeting UCHL3 attenuates pathological markers in neuronal models of Huntington's disease.

Abstract

Huntington's disease is an autosomal dominant neurodegenerative disease with a well-characterized genetic aetiology of a CAG expansion mutation in the huntingtin (HTT) gene, yet it remains without a cure. The hallmark of Huntington's disease is the accumulation of intraneuronal aggregates of mutant HTT protein and polyglutamine (polyQ)-containing fragments, which causes impaired proteostasis and is an important Huntington's disease 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 used Huntington's disease models, including primary mouse neurons, patient fibroblasts and patient-derived medium spiny neurons, 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 Huntington's disease medium spiny neurons. These results provide a foundation for further exploration of UCHL3 inhibitors in the context of Huntington's disease and underscore the biological connection between cancer and neurodegeneration for drug repurposing strategies.