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However, the factors that regulate \u03b1-Syn pathology and nigrostriatal dopaminergic degeneration remain poorly understood. Previous studies demonstrate cholesterol 24-hydroxylase (CYP46A1) increases the risk for PD. Moreover, 24-hydroxycholesterol (24-OHC), a brain-specific oxysterol that is catalyzed by CYP46A1, is elevated in the cerebrospinal fluid of PD patients. Herein, we show that the levels of CYP46A1 and 24-OHC are elevated in PD patients and increase with age in a mouse model. Overexpression of CYP46A1 intensifies \u03b1-Syn pathology, whereas genetic removal of CYP46A1 attenuates \u03b1-Syn neurotoxicity and nigrostriatal dopaminergic degeneration in the brain. Moreover, supplementation with exogenous 24-OHC exacerbates the mitochondrial dysfunction induced by \u03b1-Syn fibrils. Intracerebral injection of 24-OHC enhances the spread of \u03b1-Syn pathology and dopaminergic neurodegeneration via elevated X-box binding protein 1 (XBP1) and lymphocyte-activation gene 3 (LAG3) levels. Thus, elevated CYP46A1 and 24-OHC promote neurotoxicity and the spread of \u03b1-Syn via the XBP1\u2013LAG3 axis. Strategies aimed at inhibiting the CYP46A1-24-OHC axis and LAG3 could hold promise as disease-modifying therapies for PD.<\/jats:p>","DOI":"10.1371\/journal.pbio.3002974","type":"journal-article","created":{"date-parts":[[2025,2,18]],"date-time":"2025-02-18T18:27:13Z","timestamp":1739903233000},"page":"e3002974","update-policy":"https:\/\/doi.org\/10.1371\/journal.pbio.corrections_policy","source":"Crossref","is-referenced-by-count":26,"title":["The cholesterol 24-hydroxylase CYP46A1 promotes \u03b1-synuclein pathology in Parkinson\u2019s 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