ArticleProceedings of the National Academy of Sciences of the United States of America2023
LRRK2 suppresses lysosome degradative activity in macrophages and microglia through MiT-TFE transcription factor inhibition.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 48 papers.
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Who cites it
48 citing papers in PubMed, 67 citations in OpenAlex.
- LRRK2-targeting antisense oligonucleotide in Parkinson's disease: a phase 1 randomized controlled trial.Nature medicine · 2026Trial
- Lysosomal dysfunction in neurodegenerative disease.Nature reviews. Neurology · 2026Review
- Disrupted TFEB/GDNF-cAMP/ATP Coupling Underlies Astrocytic Dysfunction and Depression in LRRK2 G2019S Parkinson's Mice.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Retromer-targeted therapy for neurodegenerative diseases.Molecular neurodegeneration · 2026Review
- The Parkinson's disease-linked G2019S mutation of LRRK2 increases NADPH oxidase-2 activity in neutrophils for superior control of bacterial infections.Cellular & molecular immunology · 2026Article
- LRRK2: Molecular Mechanisms in Parkinson's Disease.International journal of molecular sciences · 2026Review
- The LRRK2 G2019S variant rewires Rab GTPase phosphorylation after lysosomal damage and promotes cell death in human macrophages.Journal of cell science · 2026Article
- TFE3 Regulates Microglial Phagocytosis and Inflammation in MPTP-induced Parkinson's Disease.Molecular neurobiology · 2026Article
- The emerging role and therapeutic targeting of autophagy-lysosome pathway in the pathogenesis of Parkinson's disease.Translational neurodegeneration · 2026Review
- Article
- Tissue-specific transcriptional epistasis between Prkn and Lrrk2 during mycobacterial infection.Mammalian genome : official journal of the International Mammalian Genome Society · 2026Article
- LRRK2 kinase mediates increased GCase activity in microglia in response to IFNγ-induced proinflammatory stimulation.NPJ Parkinson's disease · 2026Article
- Role of LRRK2 in physiological activities, diseases, and therapy.Chinese medical journal · 2026Review
- "Micro-managing" immune activation and protein turnover: microglial lysosomes in the context of health and disease.NPJ dementia · 2026Review
- Microglia heterogeneity and therapeutic strategies in Parkinson's disease.Frontiers in immunology · 2026Review
- RNA networks of lysosomal-related biomarkers in Parkinson's disease and their correlations with freezing of gait-associated genes.Frontiers in genetics · 2026Article
- Integrated Biofluid Proteomics Identified Dynamic Functional Biomarkers ofmedRxiv : the preprint server for health sciences · 2025Article
- GPNMB is a biomarker for lysosomal dysfunction and is secreted via LRRK2-modulated lysosomal exocytosis.Science advances · 2025Article
- RNASEH2C enhances TRAF3IP1 to degrade RAI14 in lysosomes thus hindering macrophage antigen presentation and advancing liver cancer.Cell death & disease · 2025Article
- The E193K LRRK2 mutation interferes with the autophagosome processing through the impairment of the LRRK2-Dynein-1 complex.Scientific reports · 2025Article
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Authors and funding
2 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Cells maintain optimal levels of lysosome degradative activity to protect against pathogens, clear waste, and generate nutrients. Here, we show that LRRK2, a protein that is tightly linked to Parkinson's disease, negatively regulates lysosome degradative activity in macrophages and microglia via a transcriptional mechanism. Depletion of LRRK2 and inhibition of LRRK2 kinase activity enhanced lysosomal proteolytic activity and increased the expression of multiple lysosomal hydrolases. Conversely, the kinase hyperactive LRRK2 G2019S Parkinson's disease mutant suppressed lysosomal degradative activity and gene expression. We identified MiT-TFE transcription factors (TFE3, TFEB, and MITF) as mediators of LRRK2-dependent control of lysosomal gene expression. LRRK2 negatively regulated the abundance and nuclear localization of these transcription factors and their depletion prevented LRRK2-dependent changes in lysosome protein levels. These observations define a role for LRRK2 in controlling lysosome degradative activity and support a model wherein LRRK2 hyperactivity may increase Parkinson's disease risk by suppressing lysosome degradative activity.
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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.