{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T04:21:04Z","timestamp":1789618864826,"version":"build-2803163510"},"posted":{"date-parts":[[2025,9,28]]},"group-title":"Neuroscience","reference-count":132,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,9,28]],"date-time":"2025-09-28T00:00:00Z","timestamp":1759017600000},"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":["NS110188"],"award-info":[{"award-number":["NS110188"]}],"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":["AG082373"],"award-info":[{"award-number":["AG082373"]}],"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":["AG077269"],"award-info":[{"award-number":["AG077269"]}],"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":["ES033625"],"award-info":[{"award-number":["ES033625"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000864","name":"Michael J. Fox Foundation","doi-asserted-by":"crossref","award":["MJFF-023425"],"award-info":[{"award-number":["MJFF-023425"]}],"id":[{"id":"10.13039\/100000864","id-type":"DOI","asserted-by":"crossref"}]},{"id":[{"id":"https:\/\/ror.org\/04byxyr05","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,2,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Iron accumulation is a hallmark of sporadic and familial Parkinson\u2019s disease (PD) and correlates with clinical motor symptom severity. The biochemical mechanisms driving iron dyshomeostasis in PD brain and whether these are early or late events in the neurodegenerative process remain unknown. Nigral iron levels in LRRK2-PD patients have been reported to be even higher than in idiopathic PD, and greater in non-manifesting LRRK2 carriers than controls, suggesting that iron accumulation precedes clinical onset in LRRK2-associated PD. However, the cells affected and mechanisms governing iron dyshomeostasis in PD remain unclear.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>Here, we investigated multiple independent measures of iron homeostasis in iPSCs, iPSC-derived cortical and dopaminergic neurons, and astrocytes from control and PD patient-derived iPSCs and an isogenic iPSC panel of three independent pathogenic PD mutations. High-content and super-resolution microscopy of iron-specific probes and ICP-MS were used to determine iron content and distribution across different cell types and LRRK2 genotypes. The upstream effectors and downstream consequences of iron dyshomeostasis on ferroptosis signaling were also examined.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>We found that heterozygous LRRK2 mutations dysregulate cellular iron levels across iPSCs, neurons and astrocytes, in a kinase-dependent manner. Lysosomal ferrous iron was specifically and consistently elevated across iPSCs, iPSC-derived cortical and dopaminergic neurons, and astrocytes carrying LRRK2 mutations and rescued by treatment with the selective LRRK2 inhibitor, MLi-2. Importantly, we show that lipid peroxidation and ROS levels are elevated in isogenic LRRK2 mutant neurons, while iron chelation or MLi-2 reduced LRRK2-dependent ROS damage. LRRK2 regulates the function of over a dozen Rab GTPase proteins through direct phosphorylation, and our prior work revealed a unique correlation with Rab8a trafficking and iron. Here, we report that CRISPR\/Cas9 knockout of Rab8a recapitulates LRRK2-driven effects on intracellular iron in different cell types and that exogenous Rab8a normalizes lysosomal iron levels in R1441C LRRK2 iPSCs.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>Together, our findings demonstrate that LRRK2 mutations disrupt iron homeostasis across multiple cell types, including dopaminergic neurons, and establish a discrete biochemical pathway linking LRRK2 and vulnerability to ferroptosis signaling.<\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2025.09.26.678370","type":"posted-content","created":{"date-parts":[[2025,9,28]],"date-time":"2025-09-28T21:35:12Z","timestamp":1759095312000},"source":"Crossref","is-referenced-by-count":4,"title":["Parkinson\u2019s disease LRRK2 mutations dysregulate iron homeostasis and promote oxidative stress and ferroptosis in human neurons and astrocytes"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5546-7084","authenticated-orcid":false,"given":"Adamantios","family":"Mamais","sequence":"first","affiliation":[{"name":"Center for Translational Research in Neurodegenerative Disease, Fixel Institute for Neurologic Diseases, Department of Neurology, University of Florida, Gainesville, FL, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"Jr","given":"Richard D.","family":"Batchelor","sequence":"additional","affiliation":[{"name":"Center for Translational Research in Neurodegenerative Disease, Fixel Institute for Neurologic Diseases, Department of Neurology, University of Florida, Gainesville, FL, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7699-8300","authenticated-orcid":false,"given":"Aravindraja","family":"Chairmandurai","sequence":"additional","affiliation":[{"name":"Center for Translational Research in Neurodegenerative Disease, Fixel Institute for Neurologic Diseases, Department of Neurology, University of Florida, Gainesville, FL, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas B.","family":"Ladd","sequence":"additional","affiliation":[{"name":"Center for Translational Research in Neurodegenerative Disease, Fixel Institute for Neurologic Diseases, Department of Neurology, University of Florida, Gainesville, FL, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Austin J.","family":"Shute","sequence":"additional","affiliation":[{"name":"Center for Translational Research in Neurodegenerative Disease, Fixel Institute for Neurologic Diseases, Department of Neurology, University of Florida, Gainesville, FL, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2975-4271","authenticated-orcid":false,"given":"Nitya","family":"Subrahmanian","sequence":"additional","affiliation":[{"name":"Center for Translational Research in Neurodegenerative Disease, Fixel Institute for Neurologic Diseases, Department of Neurology, University of Florida, Gainesville, FL, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6225-6058","authenticated-orcid":false,"given":"Nunziata","family":"Maio","sequence":"additional","affiliation":[{"name":"Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Bethesda, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5134-8929","authenticated-orcid":false,"given":"Christopher D.","family":"Vulpe","sequence":"additional","affiliation":[{"name":"Center for Environmental and Human Toxicology, Department of Physiological Sciences, College of Veterinary Medicine, University of Florida, Gainesville, FL, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2583-1578","authenticated-orcid":false,"given":"Matthew J.","family":"LaVoie","sequence":"additional","affiliation":[{"name":"Center for Translational Research in Neurodegenerative Disease, Fixel Institute for Neurologic Diseases, Department of Neurology, University of Florida, Gainesville, FL, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026021601200492000_2025.09.26.678370v2.1","doi-asserted-by":"crossref","unstructured":"Ayton S , Lei P. 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Chemically Induced Models of Parkinson\u2019s Disease: History and Perspectives for the Involvement of Ferroptosis. Frontiers in Cellular Neuroscience [Internet]. 2020 [cited 2023 Jan 1];14. 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Phosphoproteomics reveals that Parkinson\u2019s disease kinase LRRK2 regulates a subset of Rab GTPases. eLife [Internet]. 2016 Jan 29 [cited 2016 Apr 28];5. 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