{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T10:15:10Z","timestamp":1785406510210,"version":"3.56.0"},"posted":{"date-parts":[[2026,4,6]]},"group-title":"Neuroscience","reference-count":86,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,4,6]],"date-time":"2026-04-06T00:00:00Z","timestamp":1775433600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"award":["ASAP-024297"],"award-info":[{"award-number":["ASAP-024297"]}],"id":[{"id":"https:\/\/ror.org\/03zj4c476","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000049","name":"National Institute on Aging","doi-asserted-by":"crossref","award":["R01NS114239"],"award-info":[{"award-number":["R01NS114239"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,4,6]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>\n                  Aging is the strongest risk factor for neurodegeneration, yet how the human brain ages remains poorly understood. Loss-of-function (LOF) variants in\n                  <jats:italic>ATP13A2<\/jats:italic>\n                  cause severe juvenile-onset Parkinson\u2019s disease, providing a window into the mechanisms that accelerate age-related neurodegeneration. ATP13A2-LOF causes lysosomal polyamine sequestration, but how this promotes pathogenesis remains unclear. We discovered that ATP13A2-LOF depletes cytosolic polyamines in astrocytes, triggering compensatory upregulation of\n                  <jats:italic>de novo<\/jats:italic>\n                  polyamine biosynthesis, which diverts S-adenosyl methionine (SAM) from DNA and histone methylation, leading to increased chromatin accessibility and epigenetic reprogramming of astrocytes into a neuroinflammatory state that releases neurotoxic cytokines that promote dopaminergic neuron death. In ATP13A2 knockout mice and human models, we find that genetic and pharmacological inhibition of SAM utilization in polyamine biosynthesis prevents astrocytic epigenetic reprogramming and promotes dopaminergic neuron survival. These findings reveal a direct link between polyamine metabolism, epigenetic dysfunction, and neurotoxic inflammation, uncovering new therapeutic opportunities in Parkinson\u2019s disease.\n                <\/jats:p>","DOI":"10.64898\/2026.04.02.716164","type":"posted-content","created":{"date-parts":[[2026,4,6]],"date-time":"2026-04-06T22:55:13Z","timestamp":1775516113000},"source":"Crossref","is-referenced-by-count":2,"title":["ATP13A2 Loss of Function-Driven Polyamine Dysregulation Induces SAM Depletion and Epigenetic Astrocyte Toxicity"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9849-2423","authenticated-orcid":false,"given":"Elena","family":"Coccia","sequence":"first","affiliation":[{"name":"Nash Family Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA"},{"name":"Ronald M. 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