{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T15:09:50Z","timestamp":1792076990901,"version":"4.4.0"},"reference-count":41,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"857","funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82373851"],"award-info":[{"award-number":["82373851"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82173797"],"award-info":[{"award-number":["82173797"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82204357"],"award-info":[{"award-number":["82204357"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["U25A20182"],"award-info":[{"award-number":["U25A20182"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002949","name":"Government of Jiangsu Province","doi-asserted-by":"publisher","award":["BK20231267"],"award-info":[{"award-number":["BK20231267"]}],"id":[{"id":"10.13039\/501100002949","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002949","name":"Government of Jiangsu Province","doi-asserted-by":"publisher","award":["BK20241858"],"award-info":[{"award-number":["BK20241858"]}],"id":[{"id":"10.13039\/501100002949","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002949","name":"Government of Jiangsu Province","doi-asserted-by":"publisher","award":["BM2024001"],"award-info":[{"award-number":["BM2024001"]}],"id":[{"id":"10.13039\/501100002949","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012166","name":"National key R&D program of China","doi-asserted-by":"crossref","award":["2021ZD0202903"],"award-info":[{"award-number":["2021ZD0202903"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Transl. Med."],"published-print":{"date-parts":[[2026,7,8]]},"abstract":"<jats:p>\n                    Insufficient understanding of \u03b1-synuclein turnover mechanisms has impeded successful clinical translation for Parkinson\u2019s disease (PD). Here, we pinpointed cholesterol 25-hydroxylase (CH25H) as a pivotal regulator of \u03b1-synuclein degradation. Through bulk RNA sequencing of substantia nigra tissue from the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD, along with reanalysis of published datasets from induced pluripotent stem cell\u2013derived astrocytes of patients with PD, we observed an elevated CH25H expression in PD-associated astrocytes. This finding was validated by combined fluorescence in situ hybridization for\n                    <jats:italic toggle=\"yes\">Ch25h<\/jats:italic>\n                    and immunofluorescence staining for GFAP in mouse substantia nigra sections. Conditional knockout or knockdown of astrocytic\n                    <jats:italic toggle=\"yes\">Ch25h<\/jats:italic>\n                    alleviated PD-like motor deficits and reduced dopaminergic neuronal loss in MPTP and \u03b1-synuclein preformed fibril (PFF) mouse models. Using 4D label-free proteomics and molecular docking approaches, we uncovered a shared binding domain on p62 where both CH25H and \u03b1-synuclein interact. Proximity ligation assays in cultured astrocytes showed that\n                    <jats:italic toggle=\"yes\">Ch25h<\/jats:italic>\n                    overexpression promoted formation of p62\/CH25H complex, whereas it inhibited p62\/\u03b1-synuclein interaction. Conversely,\n                    <jats:italic toggle=\"yes\">Ch25h<\/jats:italic>\n                    knockdown enhanced p62\/\u03b1-synuclein complex formation and facilitated \u03b1-synuclein degradation. 25-Hydroxycholesterol, the enzymatic by-product of CH25H, did not affect the expression of \u03b1-synuclein in astrocytes, suggesting an activity-independent influence of CH25H on \u03b1-synuclein clearance. In addition, treatment with a p62 polypeptide (60 to 90 amino acids) effectively facilitated \u03b1-synuclein clearance by sequestering free CH25H in both cultured astrocytes and mice in the PFF model. Collectively, our study provides insights into the mechanisms underlying \u03b1-synuclein turnover and suggests promising avenues for disease-modifying interventions in synucleinopathies.\n                  <\/jats:p>","DOI":"10.1126\/scitranslmed.adv7705","type":"journal-article","created":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T17:58:12Z","timestamp":1783533492000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":3,"title":["Targeting of CH25H to boost p62-dependent autophagic degradation of \u03b1-synuclein in cell and mouse models of Parkinson\u2019s disease"],"prefix":"10.1126","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-3327-2016","authenticated-orcid":true,"given":"Xiwei","family":"Zhang","sequence":"first","affiliation":[{"name":"Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, Nanjing 211166, China."},{"name":"Changzhou Second People\u2019s Hospital, Changzhou Medical Center, Nanjing Medical University, Changzhou 213000, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruixue","family":"Han","sequence":"additional","affiliation":[{"name":"Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, Nanjing 211166, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen","family":"Zhang","sequence":"additional","affiliation":[{"name":"Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, Nanjing 211166, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shenhan","family":"Xu","sequence":"additional","affiliation":[{"name":"Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, Nanjing 211166, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yueping","family":"Wang","sequence":"additional","affiliation":[{"name":"Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, Nanjing 211166, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min","family":"Wang","sequence":"additional","affiliation":[{"name":"Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, Nanjing 211166, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2504-7406","authenticated-orcid":true,"given":"Renhong","family":"Du","sequence":"additional","affiliation":[{"name":"Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, Nanjing 211166, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4243-2330","authenticated-orcid":true,"given":"Yang","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Nanjing University of Chinese Medicine, Nanjing 210023, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luping","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics, School of Pharmacy, Nanjing Medical University, Nanjing 211166 China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cong","family":"Wang","sequence":"additional","affiliation":[{"name":"Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, Nanjing 211166, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kezhong","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Neurology, First Affiliated Hospital of Nanjing Medical University, Nanjing, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gang","family":"Hu","sequence":"additional","affiliation":[{"name":"Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, Nanjing 211166, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huae","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics, School of Pharmacy, Nanjing Medical University, Nanjing 211166 China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6493-1467","authenticated-orcid":true,"given":"Lei","family":"Cao","sequence":"additional","affiliation":[{"name":"Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, Nanjing 211166, China."},{"name":"Changzhou Second People\u2019s Hospital, Changzhou Medical Center, Nanjing Medical University, Changzhou 213000, 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