{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,3,4]],"date-time":"2026-03-04T17:18:39Z","timestamp":1772644719103,"version":"3.50.1"},"posted":{"date-parts":[[2026,3,1]]},"group-title":"Cell Biology","reference-count":117,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,3,1]],"date-time":"2026-03-01T00:00:00Z","timestamp":1772323200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["RO1NS119528"],"award-info":[{"award-number":["RO1NS119528"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["RO1NS119528-03S2"],"award-info":[{"award-number":["RO1NS119528-03S2"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,3,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>\n                  <jats:italic>LRRK2<\/jats:italic>\n                  mutations are the most common cause of autosomal-dominant Parkinson\u2019s disease (PD), with G2019S linked to both familial and sporadic PD. Although LRRK2-mediated mitochondrial DNA damage is implicated in PD, the contribution of nuclear DNA damage is less understood. Using CRISPR\/Cas9-generated LRRK2\n                  <jats:sup>G2019S\/G2019S<\/jats:sup>\n                  knock-in cells, we discovered increased sensitivity to oxidative and alkylating DNA-damaging agents compared to wild-type, consistent with compromised tolerance\/repair of lesions processed by base excision repair (BER). The oxRADD assay revealed elevated endogenous oxidative nuclear base damage in\n                  <jats:italic>LRRK2<\/jats:italic>\n                  mutant cells. Concomitantly, PARP1-dependent poly(ADP-ribose) (PAR) levels were markedly increased, with chromatin enrichment of PARP1 and BER factors (XRCC1, DNA ligase III) only in LRRK2\n                  <jats:sup>G2019S\/G2019S<\/jats:sup>\n                  cells, indicating BER initiation, without successful resolution. LRRK2\n                  <jats:sup>G2019S\/G2019S<\/jats:sup>\n                  cells displayed synthetic lethality with PARP-trapping inhibitors (olaparib) but tolerated PARP1 knockdown, suggesting cytotoxicity from stabilized PARP-DNA complexes rather than loss of catalytic activity. The SOD\/catalase mimetic EUK-134 abrogated LRRK2 G2019S-dependent PAR accumulation, whereas the mitochondrial complex I inhibitor rotenone exacerbated PAR levels, linking reactive oxygen species (ROS) to BER dysfunction and PARP1 hyperactivation. Overall, we have identified a ROS-dependent PARP1 hyperactivation pathway that underlies LRRK2 G2019S-associated cellular vulnerability.\n                <\/jats:p>","DOI":"10.64898\/2026.02.27.708379","type":"posted-content","created":{"date-parts":[[2026,3,2]],"date-time":"2026-03-02T00:20:14Z","timestamp":1772410814000},"source":"Crossref","is-referenced-by-count":0,"title":["Parkinson\u2019s disease linked LRRK2 G2019S drives oxidative nuclear DNA damage and PARP1 hyperactive signaling"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4125-4264","authenticated-orcid":false,"given":"Jennifer","family":"Liu","sequence":"first","affiliation":[{"name":"Departments of Neurology and Pathology, Duke University School of Medicine, Durham, North Carolina, 27710, USA"},{"name":"Duke Center for Neurodegeneration and Neurotherapeutics, Duke University, Durham, North Carolina, 27710, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Claudia 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Duke University, Durham, North Carolina, 27710, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carolyn","family":"Chen","sequence":"additional","affiliation":[{"name":"Departments of Neurology and Pathology, Duke University School of Medicine, Durham, North Carolina, 27710, USA"},{"name":"Duke Center for Neurodegeneration and Neurotherapeutics, Duke University, Durham, North Carolina, 27710, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carlos","family":"Montes","sequence":"additional","affiliation":[{"name":"Departments of Neurology and Pathology, Duke University School of Medicine, Durham, North Carolina, 27710, USA"},{"name":"Duke Center for Neurodegeneration and Neurotherapeutics, Duke University, Durham, North Carolina, 27710, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lingyan","family":"Ma","sequence":"additional","affiliation":[{"name":"Departments of Neurology and Pathology, Duke University School of 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