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Here, we identified DNAJB1 (DJ1) as endogenous substrate of CRBN and report how CRBN influences the aggregation and toxicity of alpha-synuclein (\u03b1-SYN) <jats:italic>via<\/jats:italic> modulation of DJ1. CRBN interferes with molecular activities of DJ1 in vitro, in cells, and in vivo resulting in a reduced disaggregation of \u03b1-SYN fibrils, increased formation of preformed fibrils (PFFs) of \u03b1-SYN, and high susceptibility of mice to MPTP and PFF-induced neurotoxicity. Depletion of <jats:italic>Crbn<\/jats:italic> improves the behavioral and biochemical responses of mice towards neurotoxic insult. Finally, we designed a peptide inhibitor to inhibit the recruitment of DJ1 to CRBN for ubiquitination, resulting in an enhanced supply of DJ1 to counteract the toxicity of aggregated \u03b1-SYN. Our data has important implications for development of CRBN-targeting therapies that could prevent or delay progression of neurodegenerative synucleinopathy.<\/jats:p>","DOI":"10.1038\/s41531-024-00801-3","type":"journal-article","created":{"date-parts":[[2024,10,23]],"date-time":"2024-10-23T12:02:54Z","timestamp":1729684974000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["CRBN modulates synuclein fibrillation via degradation of DNAJB1 in mouse model of Parkinson disease"],"prefix":"10.1038","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3649-0673","authenticated-orcid":false,"given":"Uroos","family":"Akber","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jun-Hyung","family":"Jung","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-4851-3390","authenticated-orcid":false,"given":"Heewoong","family":"Yoon","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiwon","family":"Seo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0209-1412","authenticated-orcid":false,"given":"Chul-Seung","family":"Park","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2024,10,23]]},"reference":[{"key":"801_CR1","doi-asserted-by":"publisher","first-page":"1345","DOI":"10.1126\/science.1177319","volume":"327","author":"T Ito","year":"2010","unstructured":"Ito, T. et al. 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