ArticlePLoS biology2021
Mutations in LRRK2 linked to Parkinson disease sequester Rab8a to damaged lysosomes and regulate transferrin-mediated iron uptake in microglia.
Article in PLoS biology, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 52 papers.
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Who cites it
52 citing papers in PubMed, 80 citations in OpenAlex.
- Leucine-rich repeat kinase 2 (LRRK2): balancing cellular homeostasis and Parkinson's disease (PD) pathogenesis.Annals of medicine · 2026Review
- An LRRK2 variant blocks NCOA4 trafficking upon iron overload, leading to ferroptotic death.Journal of cell science · 2026Article
- The C9orf72/SMCR8 complex maintains microglial homeostasis via RAB8A-ESCRT-mediated lysosomal repair.The EMBO journal · 2026Article
- Ferritin in ferroptosis: Implications for neurodegenerative diseases (Review).International journal of molecular medicine · 2026Review
- Rab8a dysregulation in Parkinson's disease: A convergence of genetic and molecular pathologies.Molecular biology reports · 2026Review
- Role of Microglial Dysfunction in Parkinson's Disease: From Multifactorial Causes to Neurodegeneration.Neuroscience bulletin · 2026Review
- Induced Pluripotent Stem Cells Derived Cellular Models for Investigating Parkinson's Disease Pathogenesis and Drug Screening.Stem cell reviews and reports · 2025Review
- Parkinson's disease LRRK2 mutations dysregulate iron homeostasis and promote oxidative stress and ferroptosis in human neurons and astrocytes.bioRxiv : the preprint server for biology · 2025Article
- Regulation of LRRK2 activity by metabolic stress and heavy metal exposure.Brain research · 2025Article
- Recent advances in targeting LRRK2 for Parkinson's disease treatment.Journal of translational medicine · 2025Review
- A new LRRK2 variant in a family with Parkinson's disease affects binding to RAB8A.NPJ Parkinson's disease · 2025Article
- Current Development of iPSC-Based Modeling in Neurodegenerative Diseases.International journal of molecular sciences · 2025Review
- Homeostasis and metabolism of iron and other metal ions in neurodegenerative diseases.Signal transduction and targeted therapy · 2025Review
- Induced pluripotent stem cell-derived macrophages as a platform for modelling human disease.Nature reviews. Immunology · 2025Review
- From pathogenesis to treatment: the emerging role of ferroptosis in Parkinson's disease.Frontiers in immunology · 2025Review
- Visualizing alpha-synuclein and iron deposition in M83 mouse model of Parkinson's disease in vivo.Brain pathology (Zurich, Switzerland) · 2024Article
- LRRK2 in Parkinson's disease: upstream regulation and therapeutic targeting.Trends in molecular medicine · 2024Review
- Parkinson's-linked LRRK2-G2019S derails AMPAR trafficking, mobility, and composition in striatum with cell-type and subunit specificity.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- RAB3 phosphorylation by pathogenic LRRK2 impairs trafficking of synaptic vesicle precursors.The Journal of cell biology · 2024Article
- LRRK2 kinase inhibition reverses G2019S mutation-dependent effects on tau pathology progression.Translational neurodegeneration · 2024Article
Corrections and comments
- Erratum issued
Authors and funding
19 authors at 7 institutions in 2 countries.
Funding
Abstract
Mutations in leucine-rich repeat kinase 2 (LRRK2) cause autosomal dominant Parkinson disease (PD), while polymorphic LRRK2 variants are associated with sporadic PD. PD-linked mutations increase LRRK2 kinase activity and induce neurotoxicity in vitro and in vivo. The small GTPase Rab8a is a LRRK2 kinase substrate and is involved in receptor-mediated recycling and endocytic trafficking of transferrin, but the effect of PD-linked LRRK2 mutations on the function of Rab8a is poorly understood. Here, we show that gain-of-function mutations in LRRK2 induce sequestration of endogenous Rab8a to lysosomes in overexpression cell models, while pharmacological inhibition of LRRK2 kinase activity reverses this phenotype. Furthermore, we show that LRRK2 mutations drive association of endocytosed transferrin with Rab8a-positive lysosomes. LRRK2 has been nominated as an integral part of cellular responses downstream of proinflammatory signals and is activated in microglia in postmortem PD tissue. Here, we show that iPSC-derived microglia from patients carrying the most common LRRK2 mutation, G2019S, mistraffic transferrin to lysosomes proximal to the nucleus in proinflammatory conditions. Furthermore, G2019S knock-in mice show a significant increase in iron deposition in microglia following intrastriatal LPS injection compared to wild-type mice, accompanied by striatal accumulation of ferritin. Our data support a role of LRRK2 in modulating iron uptake and storage in response to proinflammatory stimuli in microglia.
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