{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,8,23]],"date-time":"2026-08-23T16:07:51Z","timestamp":1787501271643,"version":"build-2736575974"},"posted":{"date-parts":[[2025,9,6]]},"group-title":"Cell Biology","reference-count":32,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,9,6]],"date-time":"2025-09-06T00:00:00Z","timestamp":1757116800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"award":["025964"],"award-info":[{"award-number":["025964"]}],"id":[{"id":"https:\/\/ror.org\/03arq3225","id-type":"ROR","asserted-by":"publisher"}]},{"award":["AG077269"],"award-info":[{"award-number":["AG077269"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,3,5]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>\n                  Mutations that increase leucine-rich repeat kinase 2 (LRRK2) activity confer significant risk for Parkinson\u2019s disease (PD), yet incomplete disease penetrance suggest additional factors are required to manifest disease. We recently identified RAB32 Ser71Arg as a Mendelian gene for PD. Here, we establish Rab32 as a key mediator linking peripheral inflammation to Lrrk2 activation. We show that Rab32 and Rab38 expression are modestly, but inversely, correlated with their homolog Rab29.\n                  <jats:italic>In vivo<\/jats:italic>\n                  , peripheral lipopolysaccharide (LPS)-induced inflammation selectively induced Rab32 expression in midbrain Iba1\n                  <jats:sup>+<\/jats:sup>\n                  microglia but not dopaminergic neurons, where it localized to Lamp1\n                  <jats:sup>+<\/jats:sup>\n                  lysosomal compartments and correlated with Lrrk2 kinase activity. LPS similarly induces Rab32 expression in human induced pluripotent stem cell-derived microglia, demonstrating a unified biological response to inflammation across species. Promoter analysis identified Tfe3, a master regulator of lysosomal biogenesis and autophagy, as a key driver of Rab32 expression induced Lrrk2 kinase activation. During inflammation, Tfe3 translocated to the nucleus of midbrain Iba1\n                  <jats:sup>+<\/jats:sup>\n                  microglia to induce Rab32 expression and Lrrk2 kinase activity. Knockdown of Tfe3, but not Tfeb, mitigates these effects, establishing Rab32 as a physiological rheostat of Lrrk2 activity. This mechanistic pathway enables peripheral inflammation to modulate LRRK2 activity and highlights Rab32\/Tfe3 as a therapeutic targeting for neuroprotection in PD.\n                <\/jats:p>","DOI":"10.1101\/2025.09.05.674552","type":"posted-content","created":{"date-parts":[[2025,9,7]],"date-time":"2025-09-07T07:25:13Z","timestamp":1757229913000},"source":"Crossref","is-referenced-by-count":3,"title":["Peripheral inflammation mediates midbrain Lrrk2 kinase activity via Rab32 expression"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4315-0482","authenticated-orcid":false,"given":"Jordan","family":"Follett","sequence":"first","affiliation":[{"name":"Department of Neurology, McKnight Brain Institute, University of Florida, Gainesville, Florida, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isaac Bul","family":"Deng","sequence":"additional","affiliation":[{"name":"Department of Neurology, McKnight Brain Institute, University of Florida, Gainesville, Florida, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert C.","family":"Sharp","sequence":"additional","affiliation":[{"name":"Department of Neurology, McKnight Brain Institute, University of Florida, Gainesville, Florida, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shannon","family":"Wall","sequence":"additional","affiliation":[{"name":"Department of Neurology, McKnight Brain Institute, University of Florida, Gainesville, Florida, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5546-7084","authenticated-orcid":false,"given":"Adamantios","family":"Mamais","sequence":"additional","affiliation":[{"name":"Department of Neurology, McKnight Brain Institute, University of Florida, Gainesville, Florida, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1159-5321","authenticated-orcid":false,"given":"Matthew J.","family":"Farrer","sequence":"additional","affiliation":[{"name":"Department of Neurology, McKnight Brain Institute, University of Florida, Gainesville, Florida, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026030905150700000_2025.09.05.674552v2.1","doi-asserted-by":"crossref","unstructured":"H. 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