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Dysfunction of DJ\u20101 is implicated in the pathogenesis of Parkinson's disease (PD). Hyperhomocysteinemia is associated with an increased risk of PD. Here we show that homocysteine thiolactone (HTL), a reactive thioester of homocysteine (Hcy), covalently modifies DJ\u20101 on the lysine 182 (K182) residue in an age\u2010dependent manner. The N\u2010homocysteinylation (N\u2010hcy) of DJ\u20101 abolishes its neuroprotective effect against oxidative stress and mitochondrial dysfunction, exacerbating cell toxicity. Blocking the N\u2010hcy of DJ\u20101 restores its protective effect. These results indicate that the N\u2010hcy of DJ\u20101 abolishes its neuroprotective effect and promotes the progression of PD. Inhibiting the N\u2010hcy of DJ\u20101 may exert neuroprotective effect against PD.<\/jats:p>","DOI":"10.1111\/acel.14124","type":"journal-article","created":{"date-parts":[[2024,2,21]],"date-time":"2024-02-21T10:05:23Z","timestamp":1708509923000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["N\u2010homocysteinylation of DJ\u20101 promotes neurodegeneration in Parkinson's disease"],"prefix":"10.1111","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3724-8686","authenticated-orcid":false,"given":"Tao","family":"Guo","sequence":"first","affiliation":[{"name":"Department of Neurology Renmin Hospital of Wuhan University  Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lingyan","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Neurology Renmin Hospital of Wuhan University  Wuhan 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