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Despite evidence for a scaffolding role for HTT in membrane-related processes such as endocytosis, vesicle transport, and vesicle fusion, it remains unclear how polyQ-expansion alters membrane binding during these processes. Using quantitative Mass Spectrometry-based proteomics on HTT-containing light vesicle membranes isolated from healthy and HD iPSC-derived neurons, we found significant changes in the proteome and kinome of signal transduction, neuronal translation, trafficking, and axon guidance-related processes. Through a combination of in vitro kinase assays, <jats:italic>Drosophila<\/jats:italic> genetics, and pharmacological inhibitors, we identified that GSK3\u03b2 and ERK1 phosphorylate HTT and that these events play distinct and opposing roles during HD with inhibition of GSK3\u03b2 decreasing polyQ-mediated axonal transport defects and neuronal cell death, while inhibition of ERK enhancing these phenotypes. Together, this work proposes two novel pathways in which GSK3\u03b2 phosphorylation events exacerbate and ERK phosphorylation events mitigate HD-dependent neuronal dysfunction highlighting a highly druggable pathway for targeted therapeutics using already available small molecules.<\/jats:p>","DOI":"10.1038\/s41419-025-07524-0","type":"journal-article","created":{"date-parts":[[2025,4,22]],"date-time":"2025-04-22T13:31:08Z","timestamp":1745328668000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Opposing roles for GSK3\u03b2 and ERK1-dependent phosphorylation of huntingtin during neuronal dysfunction and cell death in Huntington\u2019s disease"],"prefix":"10.1038","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0692-0241","authenticated-orcid":false,"given":"Thomas J.","family":"Krzystek","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rasika","family":"Rathnayake","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jia","family":"Zeng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gary","family":"Iacobucci","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3611-9295","authenticated-orcid":false,"given":"Michael C.","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8776-9397","authenticated-orcid":false,"given":"Shermali","family":"Gunawardena","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,4,22]]},"reference":[{"key":"7524_CR1","doi-asserted-by":"publisher","first-page":"985","DOI":"10.1016\/0896-6273(93)90127-D","volume":"11","author":"SH Li","year":"1993","unstructured":"Li SH, Schilling G, Young WS 3rd, Li XJ, Margolis RL, Stine OC, et al. 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