ArticleBrain : a journal of neurology2018
Mutant LRRK2 mediates peripheral and central immune responses leading to neurodegeneration in vivo.
Article in Brain : a journal of neurology, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 90 papers, 2 of them syntheses that pooled it.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
90 citing papers in PubMed, 2 syntheses or guidelines pooled it, 151 citations in OpenAlex.
- Molecular Pathways Involved in LRRK2-Linked Parkinson's Disease: A Systematic Review.International journal of molecular sciences · 2022Pooled it
- Molecular Footprints of the Immune Assault on Pancreatic Beta Cells in Type 1 Diabetes.Frontiers in endocrinology · 2020Pooled it
- Regulator of G protein signaling 10: a critical regulator of chronic systemic inflammation in parkinson's disease.Journal of neuroinflammation · 2026Review
- ATP13A2 restrains macrophage NLRP3 inflammasome activation to repress neurodegeneration via modulating mitochondrial homeostasis.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Inflammatory signaling differentially changes chromatin accessibility and gene expression of the PD- associated kinase LRRK2 between human and mice.Molecular neurodegeneration · 2026Article
- In vivo Proximity & Spatial Proteomics with CRISPR Screening Identify STXBP1 as a Protective Modifier of α-synuclein Toxicity in Dopamine Neurons.bioRxiv : the preprint server for biology · 2026Article
- Unraveling the intersection of aging and Parkinson's disease: a collaborative roadmap for advancing research models.NPJ Parkinson's disease · 2026Review
- Inflammatory signaling differentially changes chromatin accessibility and gene expression of the PD- associated kinase LRRK2 between human and mice.bioRxiv : the preprint server for biology · 2026Article
- The Parkinson's disease-associated LRRK2-G2019S variant restricts serine metabolism, leading to microglial inflammation and dopaminergic neuron degeneration.Journal of neuroinflammation · 2025Article
- "Recommendations for clinical study protocols for immune and inflammatory profiling in Parkinson's disease".NPJ Parkinson's disease · 2025Review
- LRRK2-mutant microglia and neuromelanin synergize to drive dopaminergic neurodegeneration in an iPSC-based Parkinson's disease model.Communications biology · 2025Article
- Recent advances in targeting LRRK2 for Parkinson's disease treatment.Journal of translational medicine · 2025Review
- Environmental exposures and familial background alter the induction of neuropathology and inflammation after SARS-CoV-2 infection.NPJ Parkinson's disease · 2025Article
- Environmental Factors Exacerbate Parkinsonian Phenotypes in an Asian-Specific Knock-In LRRK2 Risk Variant in Mice.International journal of molecular sciences · 2025Article
- Short-term lipopolysaccharide treatment leads to astrocyte activation in LRRK2 G2019S knock-in mice without loss of dopaminergic neurons.BMC neuroscience · 2025Article
- Unraveling the Role of Proteinopathies in Parasitic Infections.Biomedicines · 2025Review
- Exploring LRRK2-dependent Mechanisms in Parkinson's Disease Therapy.CNS & neurological disorders drug targets · 2025Review
- TheScience translational medicine · 2024Article
- Transcriptomics and weighted protein network analyses of the LRRK2 protein interactome reveal distinct molecular signatures for sporadic and LRRK2 Parkinson's Disease.NPJ Parkinson's disease · 2024Article
- Single molecule array measures of LRRK2 kinase activity in serum link Parkinson's disease severity to peripheral inflammation.Molecular neurodegeneration · 2024Article
30 more citing papers are in PubMed but not listed here.
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Authors and funding
10 authors at 1 institution in 1 country.
Funding
Abstract
Missense mutations in the leucine rich repeat kinase 2 (LRRK2) gene result in late-onset Parkinson's disease. The incomplete penetrance of LRRK2 mutations in humans and LRRK2 murine models of Parkinson's disease suggests that the disease may result from a complex interplay of genetic predispositions and persistent exogenous insults. Since neuroinflammation is commonly associated with the pathogenesis of Parkinson's disease, we examine a potential role of mutant LRRK2 in regulation of the immune response and inflammatory signalling in vivo. Here, we show that mice overexpressing human pathogenic LRRK2 mutations, but not wild-type mice or mice overexpressing human wild-type LRRK2 exhibit long-term lipopolysaccharide-induced nigral neuronal loss. This neurodegeneration is accompanied by an exacerbated neuroinflammation in the brain. The increased immune response in the brain of mutant mice subsequently has an effect on neurons by inducing intraneuronal LRRK2 upregulation. However, the enhanced neuroinflammation is unlikely to be triggered by dysfunctional microglia or infiltrated T cells and/or monocytes, but by peripheral circulating inflammatory molecules. Analysis of cytokine kinetics and inflammatory pathways in the peripheral immune cells demonstrates that LRRK2 mutation alters type II interferon immune response, suggesting that this increased neuroinflammatory response may arise outside the central nervous system. Overall, this study suggests that peripheral immune signalling plays an unexpected-but important-role in the regulation of neurodegeneration in LRRK2-associated Parkinson's disease, and provides new targets for interfering with the onset and progression of the disease.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.