ArticleScience translational medicine2020
LRRK2 mediates microglial neurotoxicity via NFATc2 in rodent models of synucleinopathies.
Article in Science translational medicine, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 52 papers, 1 of them a synthesis that pooled it.
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Who cites it
52 citing papers in PubMed, 1 synthesis or guideline pooled it, 78 citations in OpenAlex.
- Molecular Pathways Involved in LRRK2-Linked Parkinson's Disease: A Systematic Review.International journal of molecular sciences · 2022Pooled it
- Neuroinflammatory and Motor Alterations in LRRK2*G2019S Transgenic Mice Without Enhanced Vulnerability to Aging or Chronic MPTP-Induced Nigrostriatal Neurodegeneration.Journal of neurochemistry · 2026Article
- DYRK1A and Parkinson's disease, facts and hypotheses.Neurobiology of disease · 2026Review
- PINK1 loss in astrocytes triggers inflammatory dysfunction and neuronal death.bioRxiv : the preprint server for biology · 2026Article
- Dysregulation of astrocytic DNAJC6 contributes to sporadic Parkinson's disease pathogenesis.The Journal of clinical investigation · 2026Article
- LRRK2 as a Potential Disease-Modifying Target in Sporadic Parkinson's Disease.Movement disorders : official journal of the Movement Disorder Society · 2026Review
- Integrating polygenic signals and single-cell multiomics identifies cell-type-specific regulomes critical for immune- and aging-related diseases.Nature aging · 2026Article
- Differential microglial responses to structurally distinct alpha-synuclein polymorphs.Molecular brain · 2025Article
- Enhanced Selenium Supplement Extends Lifespan and Delays Multi-Organs Aging by Regulating the Sik1 Pathway Through Maintaining Calcium Homeostasis.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Redirecting microglia phenotype via inhibition of NFAT1 ameliorates deficits in mouse model of synucleinopathies.Experimental & molecular medicine · 2025Article
- The Parkinson's disease-associated LRRK2-G2019S variant restricts serine metabolism, leading to microglial inflammation and dopaminergic neuron degeneration.Journal of neuroinflammation · 2025Article
- LRRK2 Mediates α-Synuclein-Induced Neuroinflammation and Ferroptosis through the p62-Keap1-Nrf2 Pathway in Parkinson's Disease.Inflammation · 2025Article
- Recent advances in targeting LRRK2 for Parkinson's disease treatment.Journal of translational medicine · 2025Review
- The Neurotoxic Properties of α-synuclein Polymorphs.Experimental neurobiology · 2025Article
- The Multifaceted Role of LRRK2 in Parkinson's Disease.Brain sciences · 2025Review
- Genetic mutations in kinases: a comprehensive review on marketed inhibitors and unexplored targets in Parkinson's disease.Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology · 2025Review
- Short-term lipopolysaccharide treatment leads to astrocyte activation in LRRK2 G2019S knock-in mice without loss of dopaminergic neurons.BMC neuroscience · 2025Article
- Transcription factors in the development and treatment of immune disorders.Transcription · 2025Review
- The interplay between α-synuclein aggregation and necroptosis in Parkinson's disease: a spatiotemporal perspective.Frontiers in neuroscience · 2025Review
- LRRK2-mediated NLRC4 phosphorylation differentially regulates IL-1β/IL-18 secretion.Frontiers in immunology · 2025Article
Corrections and comments
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Authors and funding
19 authors at 5 institutions in 2 countries.
Funding
Abstract
Synucleinopathies are neurodegenerative disorders characterized by abnormal α-synuclein deposition that include Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. The pathology of these conditions also includes neuronal loss and neuroinflammation. Neuron-released α-synuclein has been shown to induce neurotoxic, proinflammatory microglial responses through Toll-like receptor 2, but the molecular mechanisms involved are poorly understood. Here, we show that leucine-rich repeat kinase 2 (LRRK2) plays a critical role in the activation of microglia by extracellular α-synuclein. Exposure to α-synuclein was found to enhance LRRK2 phosphorylation and activity in mouse primary microglia. Furthermore, genetic and pharmacological inhibition of LRRK2 markedly diminished α-synuclein-mediated microglial neurotoxicity via lowering of tumor necrosis factor-α and interleukin-6 expression in mouse cultures. We determined that LRRK2 promoted a neuroinflammatory cascade by selectively phosphorylating and inducing nuclear translocation of the immune transcription factor nuclear factor of activated T cells, cytoplasmic 2 (NFATc2). NFATc2 activation was seen in patients with synucleinopathies and in a mouse model of synucleinopathy, where administration of an LRRK2 pharmacological inhibitor restored motor behavioral deficits. Our results suggest that modulation of LRRK2 and its downstream signaling mediator NFATc2 might be therapeutic targets for treating synucleinopathies.
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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.