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The expanded proteins form pathological aggregates to disrupt neuronal functions during disease progression, suggesting the clearance of the aggregates is considered as a potential direction for development of therapy. Our previous studies have demonstrated one specific microRNA, miR-196a, downregulates mHTT aggregates and improves the pathological phenotypes in HD. However, the detailed mechanism remains unclear.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Proteomic analyses and bioinformatic tools were used to identify putative miR-196a targets in HD, and the expression of one target gene, Rad23b, was manipulated in different HD models to assess its role in mHTT aggregates.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Here, we identify Rad23b as a key target, and miR-196a directly downregulates Rad23b to reduce mHTT aggregates and toxicity. We also show Rad23b overexpression worsens mHTT pathology, while its knockdown or knockout diminishes aggregates, primarily through the ubiquitin\u2013proteasome system (UPS). Moreover, Rad23b interacts with mHTT aggregates via its ubiquitin-binding domains, and promotes their ubiquitination; however, Rad23b disrupts the chymotrypsin-like activity of UPS, and contributes to mHTT accumulation. In transgenic mouse models in vivo, Rad23b increases mHTT aggregates and cell death in brains, and also worsens motor dysfunction in HD transgenic mice.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>These findings demonstrate that critical role of Rad23b in miR-196a-reduced pathological aggregates, and highly suggest downregulating Rad23b or disrupting its interaction with mHTT may offer novel strategies to mitigate mHTT aggregates to delay disease progression.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s12929-026-01292-5","type":"journal-article","created":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T12:21:35Z","timestamp":1790252495000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["miR-196a reduces mutant Huntingtin aggregates by Rad23b-mediated degradation in Huntington\u2019s disease"],"prefix":"10.1186","volume":"33","author":[{"given":"Chih-Wei","family":"Tung","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siew Chin","family":"Chan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi-Ching","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Po-Ming","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pei-Hsun","family":"Cheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chuan-Mu","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1601-3653","authenticated-orcid":false,"given":"Shang-Hsun","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,9,24]]},"reference":[{"key":"1292_CR1","first-page":"317","volume":"26","author":"G Huntington","year":"1872","unstructured":"Huntington G. 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