{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,6,11]],"date-time":"2026-06-11T15:57:21Z","timestamp":1781193441286,"version":"3.54.1"},"posted":{"date-parts":[[2026,5,21]]},"group-title":"Neuroscience","reference-count":70,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,5,21]],"date-time":"2026-05-21T00:00:00Z","timestamp":1779321600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100017236","name":"Huffington Foundation","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100017236","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100032490","name":"Freedom Together Foundation","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100032490","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000011","name":"Howard Hughes Medical Institute","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100000011","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Research Vision at Texas Children\u2019s Hospital"},{"name":"Eunice Kennedy Shriver National Institute of Child Health and Development"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,6,8]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Astrocytes are key regulators of lipid metabolism, and dysregulated astrocytic lipid processing is implicated in Parkinson\u2019s disease (PD) pathogenesis. Our prior genome-wide screens identified ACSBG1, an astrocyte-enriched acyl-CoA synthetase, as a candidate regulator of \u03b1-synuclein (\u03b1-Syn) levels. However, how ACSBG1 links lipid reprogramming to inflammatory astrocyte activation and \u03b1-Syn pathology remains unknown. We compared the transcriptomic, cytokine, and lipid secretomes of TNF-\u03b1 and IL-1\u03b1 stimulated primary astrocytes from wild-type (WT) and\n                  <jats:italic>Acsbg1<\/jats:italic>\n                  knockout (KO) mice. In vivo, we crossed Acsbg1 KO mice with a Thy1-\u03b1-Syn PD model to assess behavior, neuroinflammation, synaptic integrity, and \u03b1-Syn levels. Following cytokine exposure,\n                  <jats:italic>Acsbg1<\/jats:italic>\n                  KO astrocytes mounted an attenuated inflammatory transcriptional response, secreting significantly fewer inflammatory mediators (e.g., IL-6, RANTES, MIP-3\u03b1) and less long-chain Sphingosine 20:1 than WT astrocytes. Importantly, exogenous Sphingosine 20:1 or cytokines from WT reactive astrocytes induced neuronal \u03b1-Syn phosphorylation (pS129).\n                  <jats:italic>In vivo, Acsbg1<\/jats:italic>\n                  deletion in Thy1-\u03b1-Syn mice reduced astrogliosis, rescued synaptic and behavioral deficits, and decreased total and pS129-\u03b1-Syn. These findings establish ACSBG1 as a key regulator of inflammatory astrocyte signaling that contributes to \u03b1-Syn phosphorylation via specific cytokine and lipid mediators, identifying ACSBG1 as a novel therapeutic target for modulating astrocyte-neuron communication in PD.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>Graphical abstract<\/jats:title>\n                  <jats:fig id=\"ufig1\" position=\"float\" fig-type=\"figure\" orientation=\"portrait\">\n                    <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"726454v2_ufig1\" position=\"float\" orientation=\"portrait\"\/>\n                  <\/jats:fig>\n                <\/jats:sec>","DOI":"10.64898\/2026.05.20.726454","type":"posted-content","created":{"date-parts":[[2026,5,22]],"date-time":"2026-05-22T03:55:14Z","timestamp":1779422114000},"source":"Crossref","is-referenced-by-count":0,"title":["Astrocytic ACSBG1 depletion improves lipid-cytokine signaling and attenuates \u03b1-Synuclein pathology in a Parkinson\u2019s disease mouse model"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3231-7371","authenticated-orcid":false,"given":"YoungDoo","family":"Kim","sequence":"first","affiliation":[{"name":"Department of Molecular and Human Genetics, Baylor College of Medicine (BCM)"},{"name":"Jan and Dan Duncan Neurological Research Institute at Texas Children\u2019s Hospital"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2003-6695","authenticated-orcid":false,"given":"Bhupesh","family":"Vaidya","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics, Baylor College of Medicine (BCM)"},{"name":"Jan and Dan Duncan Neurological Research Institute at Texas Children\u2019s 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