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Metabolic syndrome is implicated as a risk factor for PD, but the interaction between\n                    <jats:italic>G2019S LRRK2<\/jats:italic>\n                    and metabolic stress in disease pathogenesis remains unclear. We employed high-fat diet (HFD) feeding to induce metabolic syndrome in aged mutant\n                    <jats:italic>LRRK2<\/jats:italic>\n                    mice, followed by system-wide characterization, including metabolomic or proteomic profiling, and bulk or single-nucleus RNA sequencing. We find that thymidine and deoxyuridine levels are consistently reduced across tissues in\n                    <jats:italic>G2019S LRRK2<\/jats:italic>\n                    knockin mice accompanied by increased hepatic expression of thymidine phosphorylase. HFD exposure further unmasks disruptions in purine and energy metabolism in brain and lung of\n                    <jats:italic>G2019S LRRK2<\/jats:italic>\n                    knockin mice, with midbrain astrocytes and oligodendrocytes exhibiting the most pronounced impairment in oxidative phosphorylation transcriptional pathways. Our findings demonstrate that pre-existing metabolic syndrome unmasks widespread disruptions in systemic nucleotide and energy metabolism and exacerbates mitochondrial dysfunction in\n                    <jats:italic>G2019S LRRK2<\/jats:italic>\n                    knockin mice. This conditional \u201ctwo-hit\u201d phenotype underscores the critical role of environmental factors, such as diet, in revealing metabolic vulnerabilities associated with PD-linked genetic backgrounds, and provides potential metabolic targets for therapeutic intervention in PD.\n                  <\/jats:p>","DOI":"10.1038\/s41531-026-01465-x","type":"journal-article","created":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T12:27:59Z","timestamp":1783513679000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Interaction of G2019S LRRK2 and metabolic syndrome in a two-hit mouse model of Parkinson\u2019s disease: LRRK2-driven systemic depletion of pyrimidine nucleosides"],"prefix":"10.1038","volume":"12","author":[{"given":"Yue","family":"Ma","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Madalynn L.","family":"Erb","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kayla A.","family":"Sipple","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alina V.","family":"Offerman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junwei","family":"Niu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zachary B.","family":"Madaj","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhen","family":"Fu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kin H.","family":"Lau","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Darren J.","family":"Moore","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,7,8]]},"reference":[{"key":"1465_CR1","doi-asserted-by":"publisher","first-page":"896","DOI":"10.1016\/S0140-6736(14)61393-3","volume":"386","author":"LV Kalia","year":"2015","unstructured":"Kalia, L. 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