{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,5]],"date-time":"2026-06-05T09:01:32Z","timestamp":1780650092399,"version":"3.54.1"},"reference-count":30,"publisher":"Oxford University Press (OUP)","issue":"6","license":[{"start":{"date-parts":[[2026,1,24]],"date-time":"2026-01-24T00:00:00Z","timestamp":1769212800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Koret\\Taube Global Collaboration in Neurodegenerative Diseases"},{"name":"Aufzien Center for the Prevention and Treatment of Parkinson's disease"},{"name":"Healthy Longevity Research Center"},{"DOI":"10.13039\/501100005385","name":"Council for Higher Education","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100005385","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100023864","name":"National Institute on Aging","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100023864","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100001369","name":"Valley Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100001369","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,6,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Huntington\u2019s 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\u2019s 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\u2019s 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).<\/jats:p>\n                  <jats:p>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\u2019s disease models, including primary mouse neurons, patient fibroblasts and patient-derived medium spiny neurons, which are the most vulnerable to HTT polyQ toxicity.<\/jats:p>\n                  <jats:p>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\u2019s disease medium spiny neurons.<\/jats:p>\n                  <jats:p>These results provide a foundation for further exploration of UCHL3 inhibitors in the context of Huntington\u2019s disease and underscore the biological connection between cancer and neurodegeneration for drug repurposing strategies.<\/jats:p>","DOI":"10.1093\/brain\/awag028","type":"journal-article","created":{"date-parts":[[2026,1,23]],"date-time":"2026-01-23T12:41:48Z","timestamp":1769172108000},"page":"1893-1901","source":"Crossref","is-referenced-by-count":2,"title":["Targeting UCHL3 attenuates pathological markers in neuronal models of Huntington\u2019s disease"],"prefix":"10.1093","volume":"149","author":[{"given":"Hasan","family":"Ishtayeh","sequence":"first","affiliation":[{"name":"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 ,","place":["Israel"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Battistoni","sequence":"additional","affiliation":[{"name":"Buck Institute for Research on Aging , Novato, CA 94945 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sharon","family":"Pochtar","sequence":"additional","affiliation":[{"name":"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 ,","place":["Israel"]},{"name":"Sagol School of Neuroscience, Tel Aviv University , Tel Aviv 6997801 ,","place":["Israel"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tyne L M","family":"McHugh","sequence":"additional","affiliation":[{"name":"Buck Institute for Research on Aging , Novato, CA 94945 ,","place":["USA"]},{"name":"Leonard Davis School of Gerontology, University of Southern California , Los Angeles, CA 90089 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kizito-Tshitoko","family":"Tshilenge","sequence":"additional","affiliation":[{"name":"Buck Institute for Research on Aging , Novato, CA 94945 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian","family":"Rossmiller","sequence":"additional","affiliation":[{"name":"Buck Institute for Research on Aging , Novato, CA 94945 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fatima","family":"Amer-Sarsour","sequence":"additional","affiliation":[{"name":"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 ,","place":["Israel"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yevgeny","family":"Berdichevsky","sequence":"additional","affiliation":[{"name":"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 ,","place":["Israel"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noam","family":"Muchtar","sequence":"additional","affiliation":[{"name":"The Shmunis School of Biomedicine and Cancer Research, The George S. Wise Faculty for Life Sciences , Tel Aviv 6997801 ,","place":["Israel"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miguel","family":"Weil","sequence":"additional","affiliation":[{"name":"Sagol School of Neuroscience, Tel Aviv University , Tel Aviv 6997801 ,","place":["Israel"]},{"name":"The Shmunis School of Biomedicine and Cancer Research, The George S. Wise Faculty for Life Sciences , Tel Aviv 6997801 ,","place":["Israel"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9050-7977","authenticated-orcid":false,"given":"Lisa M","family":"Ellerby","sequence":"additional","affiliation":[{"name":"Buck Institute for Research on Aging , Novato, CA 94945 ,","place":["USA"]},{"name":"Leonard Davis School of Gerontology, University of Southern California , Los Angeles, CA 90089 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1253-497X","authenticated-orcid":false,"given":"Avraham","family":"Ashkenazi","sequence":"additional","affiliation":[{"name":"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 ,","place":["Israel"]},{"name":"Sagol School of Neuroscience, Tel Aviv University , Tel Aviv 6997801 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