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

Overview

1. Department of Cellular, Developmental, and Regenerative Biology, Gray School of Medical Sciences, Gray Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv 6997801, Israel
2. Buck Institute for Research on Aging, Novato, CA 94945, USA
3. Sagol School of Neuroscience, Tel Aviv University, Tel Aviv 6997801, Israel
4. Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA 90089, USA
5. The Shmunis School of Biomedicine and Cancer Research, The George S. Wise Faculty for Life Sciences, Tel Aviv 6997801, Israel

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.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Data

Datasets cited

• geo:GSE64810, at NCBI GEO; found in the text, “Analysis of UCHL3 transcript levels in HD…”

Data availability

The proteomic DAVID dataset used in this study is listed in the Supplementary material. Further requests for resources and information should be directed to the corresponding author.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Version 1, 27 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 12 authors, 4 keywords, 13 MeSH terms, 10 funders, 30 references.

Cite

This paper

Ishtayeh, H., Battistoni, E., Pochtar, S., McHugh, T. L. M., Tshilenge, K.-T., Rossmiller, B., Amer-Sarsour, F., Berdichevsky, Y., Muchtar, N., Weil, M., Ellerby, L. M., & Ashkenazi, A. (2026). Targeting UCHL3 attenuates pathological markers in neuronal models of Huntington's disease. Brain : a journal of neurology, 149(6), 1893-1901. https://doi.org/10.1093/brain/awag028

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