{"doi":"10.1101/2025.09.05.674552","title":"Peripheral inflammation mediates midbrain Lrrk2 kinase activity via Rab32 expression","abstract":"ABSTRACT Mutations that increase leucine-rich repeat kinase 2 (LRRK2) activity confer significant risk for Parkinson’s 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. In vivo , peripheral lipopolysaccharide (LPS)-induced inflammation selectively induced Rab32 expression in midbrain Iba1 + microglia but not dopaminergic neurons, where it localized to Lamp1 + 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 + 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.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":558994,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9541,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1058703,"name":"Isaac Bul Deng","orcid":"0000-0002-8088-3469","position":1,"is_corresponding":false},{"id":671168,"name":"Robert C. Sharp","orcid":"0000-0002-5167-8941","position":2,"is_corresponding":false},{"id":1059153,"name":"Shannon Wall","orcid":null,"position":3,"is_corresponding":false},{"id":236480,"name":"Adamantios Mamais","orcid":"0000-0002-5546-7084","position":4,"is_corresponding":false},{"id":17542,"name":"Matthew J. Farrer","orcid":"0000-0003-1159-5321","position":5,"is_corresponding":false},{"id":678372,"name":"Jordan Follett","orcid":"0000-0003-4315-0482","position":0,"is_corresponding":true}],"reference_count":69,"raw_metadata":null,"created_at":"2026-07-19T02:55:30.312295Z","pmid":"41846967","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}