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Fox Foundation for Parkinson's Research","doi-asserted-by":"publisher","award":["MJFF-023425"],"award-info":[{"award-number":["MJFF-023425"]}],"id":[{"id":"10.13039\/100000864","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000864","name":"Michael J. Fox Foundation for Parkinson's Research","doi-asserted-by":"publisher","award":["MJFF-023425"],"award-info":[{"award-number":["MJFF-023425"]}],"id":[{"id":"10.13039\/100000864","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009633","name":"Eunice Kennedy Shriver National Institute of Child Health and Human Development","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100009633","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Mol Neurodegeneration"],"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 human iPSCs and iPSC-derived models, including glutamatergic and dopaminergic neurons, and astrocytes, carrying pathogenic LRRK2 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. Upstream effectors and downstream consequences of iron dyshomeostasis, including oxidative stress and ferroptosis-related phenotypes were also examined.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Pathogenic heterozygous LRRK2 mutations were associated with altered iron homeostasis across multiple human cell models. Lysosomal ferrous iron was consistently elevated across iPSC-derived glutamatergic neurons, dopaminergic neurons, and astrocytes carrying LRRK2 mutations and these phenotypes were reduced by varying degrees following 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. In addition, CRISPR\/Cas9-mediated loss of Rab8a produced overlapping iron-related phenotypes, while exogenous Rab8a expression normalized lysosomal iron levels in R1441C LRRK2 iPSCs, supporting a contributory role for Rab8a-dependent trafficking in these effects.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Together, our findings show that pathogenic LRRK2 mutations converge on disrupted iron homeostasis across multiple human neural cell types, including dopaminergic neurons, and support a link between LRRK2 signaling, lysosomal iron dysregulation and ferroptosis-related stress.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s13024-026-00979-5","type":"journal-article","created":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T10:15:21Z","timestamp":1784888121000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Parkinson\u2019s disease LRRK2 mutations dysregulate iron homeostasis and promote oxidative stress and ferroptosis in human neurons and astrocytes"],"prefix":"10.1186","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5546-7084","authenticated-orcid":false,"given":"Adamantios","family":"Mamais","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"Jr","given":"Richard D.","family":"Batchelor","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aravindraja","family":"Chairmandurai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas B.","family":"Ladd","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Austin J.","family":"Shute","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nitya","family":"Subrahmanian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nunziata","family":"Maio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher D.","family":"Vulpe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew J.","family":"LaVoie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,7,24]]},"reference":[{"key":"979_CR1","doi-asserted-by":"publisher","unstructured":"Ayton S, Lei P. 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J Parkinson\u2019s Disease. 2025;15(1):72\u201386. https:\/\/doi.org\/10.1177\/1877718X241300295.","journal-title":"J Parkinson\u2019s Disease"}],"container-title":["Molecular Neurodegeneration"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s13024-026-00979-5","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13024-026-00979-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13024-026-00979-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T23:49:00Z","timestamp":1792540140000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s13024-026-00979-5"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,24]]},"references-count":131,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["979"],"URL":"https:\/\/doi.org\/10.1186\/s13024-026-00979-5","relation":{},"ISSN":["1750-1326"],"issn-type":[{"value":"1750-1326","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,24]]},"assertion":[{"value":"2 February 2026","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"10 July 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"24 July 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"Most experiments were performed using isogenic iPSC lines provided by the laboratory of Mark Cookson (National Institutes of Health) that were generated from the commercially available A18945 parental iPSC line (Thermo Fisher Scientific). Written informed consent for research was obtained from all participants in the Parkinson\u2019s Progression Markers Initiative (PPMI), a multi-center study approved by the institutional review boards at each participating site (individual IRB approval numbers are held by the originating institutions). Additional human iPSC lines were obtained from the NINDS Human Cell and Data Repository and were generated under approved institutional review board protocols with documented informed consent. All procedures involving human-derived materials were conducted in accordance with the principles of the Declaration of Helsinki.","order":1,"name":"Ethics","label":"Ethics approval and consent to participate","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"This manuscript was reviewed by the PPMI Data and Publications Committee and is permitted for publication.","order":2,"name":"Ethics","label":"Consent for publication","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare no competing interests.","order":3,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Declarations"}}],"article-number":"68"}}