{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T13:01:38Z","timestamp":1785416498480,"version":"3.56.0"},"posted":{"date-parts":[[2026,4,4]]},"group-title":"Neuroscience","reference-count":74,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,4,4]],"date-time":"2026-04-04T00:00:00Z","timestamp":1775260800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"award":["ASAP-000312"],"award-info":[{"award-number":["ASAP-000312"]}],"id":[{"id":"https:\/\/ror.org\/03zj4c476","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"crossref","award":["R01NS102735"],"award-info":[{"award-number":["R01NS102735"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,4,4]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Parkin, an E3 ubiquitin ligase encoded by\n                  <jats:italic>PARK2<\/jats:italic>\n                  , plays a key role in both hereditary and sporadic Parkinson\u2019s disease (PD), yet there are no therapies currently available that can target this important pathway. Here, we show that Parkin is critical for successful neuronal differentiation and survival, and we develop small-molecule Parkin agonists that can protect dopaminergic neurons. Upon differentiation of neural progenitor cells, loss of Parkin results in a reduced capacity to maintain neuronal cell state, dopaminergic neuronal phenotypes, and stress resistance. Moreover, Parkin loss disrupted cell morphology and the stability of neurites. Transcriptional and single-cell analyses reveal that Parkin controls critical pathways regulating stem-like cell transitions and is needed for stable neuronal maturation. We also examined the effects of FB231, a small molecule enhancer of Parkin E3 ligase activity, in models of PD. FB231 reduced pathological \u03b1-synuclein and enhanced cell survival in human iPSC-derived dopaminergic neurons treated with \u03b1-synuclein preformed fibrils. Furthermore, FB231 attenuated \u03b1-synuclein pathology and dopaminergic neurodegeneration in a gut \u03b1-synuclein murine model of PD. Our findings support that Parkin plays a crucial role in maintaining neuronal homeostasis and that pharmacologic activation of Parkin may be a promising strategy to attenuate neurodegeneration in PD.\n                <\/jats:p>","DOI":"10.64898\/2026.04.01.715918","type":"posted-content","created":{"date-parts":[[2026,4,5]],"date-time":"2026-04-05T03:25:13Z","timestamp":1775359513000},"source":"Crossref","is-referenced-by-count":0,"title":["Neural cell state modulation by\n                  <i>PARK2<\/i>\n                  and dopaminergic neuroprotection by small molecule Parkin agonism"],"prefix":"10.64898","author":[{"given":"Yongxing","family":"Gong","sequence":"first","affiliation":[{"name":"Dept. of Cancer Sciences and Global Center for Immunotherapy and Precision Immuno-Oncology, Cleveland Clinic, Cleveland, OH, USA"},{"name":"Case Western School of Medicine, Cleveland, OH, USA"},{"name":"Aligning Science Across Parkinson\u2019s Collaborative Research Network, Chevy Chase, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5960-0479","authenticated-orcid":false,"given":"Armin","family":"Bayati","sequence":"additional","affiliation":[{"name":"Aligning Science Across Parkinson\u2019s Collaborative Research Network, Chevy Chase, MD, USA"},{"name":"Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tyler J.","family":"Alban","sequence":"additional","affiliation":[{"name":"Dept. of Cancer Sciences and Global Center for Immunotherapy and Precision Immuno-Oncology, Cleveland Clinic, Cleveland, OH, USA"},{"name":"Case Western School of Medicine, Cleveland, OH, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Prerana","family":"Parthasarathy","sequence":"additional","affiliation":[{"name":"Dept. of Cancer Sciences and Global Center for Immunotherapy and Precision Immuno-Oncology, 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Hospital, Harvard Medical School, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chienwen","family":"Su","sequence":"additional","affiliation":[{"name":"Aligning Science Across Parkinson\u2019s Collaborative Research Network, Chevy Chase, MD, USA"},{"name":"Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-4227-4710","authenticated-orcid":false,"given":"Jackson G.","family":"Schumacher","sequence":"additional","affiliation":[{"name":"Aligning Science Across Parkinson\u2019s Collaborative Research Network, Chevy Chase, MD, USA"},{"name":"Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vijay","family":"Singh","sequence":"additional","affiliation":[{"name":"Aligning Science Across Parkinson\u2019s 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