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Updated: May 5, 2026
Fractionation for Resolution of Soluble and Insoluble Huntingtin Species
Published on: February 27, 2018
Targeting UCHL3 attenuates pathological markers in neuronal models of Huntington's disease
Hasan Ishtayeh1, Elena Battistoni2, Sharon Pochtar1,3
1Department 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.
Insights
Researchers found that inhibiting UCHL3, a deubiquitinating enzyme, reduces toxic protein aggregates in Huntington's disease (HD) models. This approach also enhances cellular clearance pathways and protects neurons, offering a potential new therapeutic strategy for HD.
Area of Science:
- Neurodegenerative diseases
- Molecular biology
- Drug discovery
Background:
- Huntington's disease (HD) is a fatal neurodegenerative disorder caused by a CAG expansion in the huntingtin (HTT) gene.
- Mutant HTT protein aggregates impair cellular proteostasis, representing a key therapeutic target.
- Deubiquitinating enzymes (DUBs) regulate protein clearance pathways like autophagy and the ubiquitin-proteasome system.
Purpose of the Study:
- To investigate the role of DUB UCHL3 in modulating polyglutamine (polyQ)-mediated aggregation and toxicity in Huntington's disease.
- To explore UCHL3 as a potential therapeutic target for HD, leveraging its known role in cancer.
Main Methods:
- Utilized HD models including primary mouse neurons, patient fibroblasts, and patient-derived medium spiny neurons (MSN).
- Genetically lowered UCHL3 expression and treated HD MSN with a small-molecule UCHL3 inhibitor.
- Assessed polyQ aggregate levels, autophagosome-lysosome fusion, STAT3 levels, and pathological markers.
Main Results:
- Genetic lowering of UCHL3 significantly decreased polyQ aggregates in HD models.
- Reduced UCHL3 expression increased autophagosome-lysosome fusion events, enhancing protein clearance.
- UCHL3 inhibition led to STAT3 induction, providing neuroprotection against proteotoxic stress.
- Small-molecule UCHL3 inhibition replicated these beneficial effects in HD MSN.
Conclusions:
- UCHL3 plays a critical role in modulating polyQ aggregation and toxicity in Huntington's disease.
- Inhibiting UCHL3 represents a promising therapeutic strategy for HD, potentially through enhancing cellular clearance and STAT3 signaling.
- Findings highlight the link between cancer and neurodegeneration, supporting drug repurposing for HD treatment.
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.
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