{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T08:04:08Z","timestamp":1787731448364,"version":"build-2784847793"},"reference-count":70,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2026,4,15]],"date-time":"2026-04-15T00:00:00Z","timestamp":1776211200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"JSPS KAKENHI","doi-asserted-by":"publisher","award":["23K06890"],"award-info":[{"award-number":["23K06890"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Leucine-rich repeat kinase 2 (LRRK2) is a multidomain serine\/threonine kinase and a major genetic contributor to Parkinson\u2019s disease (PD). Although LRRK2 has been extensively studied in neurodegeneration, emerging evidence indicates that it also plays a critical role in systemic metabolism. LRRK2 regulates glucose homeostasis through modulation of insulin signaling, vesicle trafficking, mitochondrial function, and inflammatory responses. Studies using LRRK2 knockout and knock-in models, including the pathogenic G2019S mutation, have revealed abnormalities in insulin sensitivity, adipose tissue inflammation, hepatic glucose production, and skeletal muscle metabolism. Mechanistically, LRRK2 phosphorylates Rab GTPases, thereby controlling insulin receptor trafficking and GLUT4 translocation. In addition, LRRK2 influences mitochondrial dynamics and reactive oxygen species production, linking metabolic stress to inflammatory signaling. Importantly, LRRK2 also regulates innate immune pathways, including TLR4\u2013NF\u03baB signaling and inflammasome activation, thereby connecting peripheral metabolic dysfunction to neuroinflammation. Here, we propose an integrated metabolic\u2013neuroinflammatory crosstalk model in which LRRK2 functions as a molecular coordinator linking peripheral metabolic dysfunction to central neurodegeneration. In this framework, systemic metabolic stress\u2014characterized by insulin resistance, chronic inflammation, advanced glycation end product (AGE) accumulation, and blood\u2013brain barrier disruption\u2014drives microglial activation and neurodegenerative processes. Understanding this systemic axis may provide new therapeutic opportunities targeting both metabolic dysfunction and neurodegeneration in PD.<\/jats:p>","DOI":"10.3390\/biom16040588","type":"journal-article","created":{"date-parts":[[2026,4,15]],"date-time":"2026-04-15T14:02:33Z","timestamp":1776261753000},"page":"588","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Leucine-Rich Repeat Kinase 2 (LRRK2) in Glucose Metabolism and Metabolic\u2013Neuroinflammatory Crosstalk"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8781-2516","authenticated-orcid":false,"given":"Fumitaka","family":"Kawakami","sequence":"first","affiliation":[{"name":"Department of Regulation Biochemistry, Graduate School of Medical Sciences, Kitasato University, 1-15-1, Kitasato, Minami-ku, Sagamihara 252-0373, Kanagawa, Japan"},{"name":"Department of Health Administration, School of Allied Health Sciences, Kitasato University, Sagamihara 252-0373, Kanagawa, Japan"},{"name":"Regenerative Medicine and Cell Design Research Facility, School of Allied Health Sciences, Kitasato University, Sagamihara 252-0373, Kanagawa, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Motoki","family":"Imai","sequence":"additional","affiliation":[{"name":"Regenerative Medicine and Cell Design Research Facility, School of Allied Health Sciences, Kitasato University, Sagamihara 252-0373, Kanagawa, Japan"},{"name":"Department of Molecular Diagnostics, School of Allied Health Sciences, Kitasato University, Sagamihara 252-0373, Kanagawa, Japan"},{"name":"Department of Applied Tumor Pathology, Graduate School of Medical Sciences, Kitasato University, Sagamihara 252-0373, Kanagawa, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masanori","family":"Ogata","sequence":"additional","affiliation":[{"name":"Regenerative Medicine and Cell Design Research Facility, School of Allied Health Sciences, Kitasato University, Sagamihara 252-0373, Kanagawa, Japan"},{"name":"Department of Physiology, School of Allied Health Sciences, Kitasato University, Sagamihara 252-0373, Kanagawa, Japan"},{"name":"Department of Brain Science, Graduate School of Medical Sciences, Kitasato University, Sagamihara 252-0373, Kanagawa, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6595-6834","authenticated-orcid":false,"given":"Toshiya","family":"Habata","sequence":"additional","affiliation":[{"name":"Regenerative Medicine and Cell Design Research Facility, School of Allied Health Sciences, Kitasato University, Sagamihara 252-0373, Kanagawa, Japan"},{"name":"Department of Brain Science, Graduate School of Medical Sciences, Kitasato University, Sagamihara 252-0373, Kanagawa, Japan"},{"name":"Department of Occupational Therapy, School of Allied Health Sciences, Kitasato University, Sagamihara 252-0373, Kanagawa, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-7722-5623","authenticated-orcid":false,"given":"Shun","family":"Tamaki","sequence":"additional","affiliation":[{"name":"Department of Regulation Biochemistry, Graduate School of Medical Sciences, Kitasato University, 1-15-1, Kitasato, Minami-ku, Sagamihara 252-0373, Kanagawa, Japan"},{"name":"Regenerative Medicine and Cell Design Research Facility, School of Allied Health Sciences, Kitasato University, Sagamihara 252-0373, Kanagawa, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rei","family":"Kawashima","sequence":"additional","affiliation":[{"name":"Department of Regulation Biochemistry, Graduate School of Medical Sciences, Kitasato University, 1-15-1, Kitasato, Minami-ku, Sagamihara 252-0373, Kanagawa, Japan"},{"name":"Regenerative Medicine and Cell Design Research Facility, School of Allied Health Sciences, Kitasato University, Sagamihara 252-0373, Kanagawa, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3272-1470","authenticated-orcid":false,"given":"Yoshifumi","family":"Kurosaki","sequence":"additional","affiliation":[{"name":"Department of Regulation Biochemistry, Graduate School of Medical Sciences, Kitasato University, 1-15-1, Kitasato, Minami-ku, Sagamihara 252-0373, Kanagawa, Japan"},{"name":"Regenerative Medicine and Cell Design Research Facility, School of Allied Health Sciences, Kitasato University, Sagamihara 252-0373, Kanagawa, Japan"},{"name":"Department of Medical Laboratory Sciences, School of Allied Health Sciences, Kitasato University, Sagamihara 252-0373, Kanagawa, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1555-6330","authenticated-orcid":false,"given":"Sayaka","family":"Miyai","sequence":"additional","affiliation":[{"name":"Regenerative Medicine and Cell Design Research Facility, School of Allied Health Sciences, Kitasato University, Sagamihara 252-0373, Kanagawa, Japan"},{"name":"Department of Medical Laboratory Sciences, School of Health Sciences, Kitasato University, Minamiuonuma 949-7241, Niigata, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3264-1155","authenticated-orcid":false,"given":"Moragot","family":"Chatatikun","sequence":"additional","affiliation":[{"name":"Department of Medical Technology, School of Allied Health Sciences, Walailak University, Nakhon Si Thammarat 80160, Thailand"},{"name":"Research Excellence Center for Innovation and Health Products (RECIHP), Walailak University, Nakhon Si Thammarat 80160, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"May Pyone","family":"Kyaw","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, University of Medicine 1, Pyae Road, Kamayut Township 11041, Yangon, Myanmar"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenichi","family":"Ohba","sequence":"additional","affiliation":[{"name":"Department of Health Administration, School of Allied Health Sciences, Kitasato University, Sagamihara 252-0373, Kanagawa, Japan"},{"name":"Regenerative Medicine and Cell Design Research Facility, School of Allied Health Sciences, Kitasato University, Sagamihara 252-0373, Kanagawa, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"599","DOI":"10.1111\/j.1365-2990.2007.00874.x","article-title":"Parkinson\u2019s disease: A dual-hit hypothesis","volume":"33","author":"Hawkes","year":"2007","journal-title":"Neuropathol. 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