ArticleScientific reports2017
The LRRK2 G2385R variant is a partial loss-of-function mutation that affects synaptic vesicle trafficking through altered protein interactions.
Article in Scientific reports, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 40 papers.
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40 citing papers in PubMed.
- Parkinson's disease-associated LRRK2 risk variant, G2385R, enhances Rab substrate phosphorylation and impairs neuronal integrity.Human molecular genetics · 2026Article
- Proximity proteomics reveals a co-evolved LRRK2-regulatory network linked to centrosomes.EMBO reports · 2026Article
- Parkinson's disease-associated LRRK2 risk variant, G2385R, enhances Rab substrate phosphorylation and impairs neuronal integrity.bioRxiv : the preprint server for biology · 2026Article
- LRRK2 kinase modulates glucose-stimulated insulin secretion via RAB8 phosphorylation and ciliogenesis.Cellular and molecular life sciences : CMLS · 2025Article
- Recent advances in targeting LRRK2 for Parkinson's disease treatment.Journal of translational medicine · 2025Review
- Association betweenFrontiers in genetics · 2025Article
- Genetic evidence for a functional association between Parkinson's disease proteins leucine-rich repeat kinase 2 andFrontiers in molecular neuroscience · 2025Article
- The senescent synapse: A look at autophagy, calcium handling, and mitochondrial bioenergetics at the synapse in ageing and Parkinson's disease.Current research in physiology · 2025Review
- Intramolecular feedback regulation of the LRRK2 Roc G domain by a LRRK2 kinase-dependent mechanism.eLife · 2024Article
- High-depth whole-genome sequencing identifies structure variants, copy number variants and short tandem repeats associated with Parkinson's disease.NPJ Parkinson's disease · 2024Article
- Cell-autonomous role of leucine-rich repeat kinase in the protection of dopaminergic neuron survival.eLife · 2024Article
- Disruption of Dopamine Homeostasis Associated with Alteration of Proteins in Synaptic Vesicles: A Putative Central Mechanism of Parkinson's Disease Pathogenesis.Aging and disease · 2024Review
- Neuroprotective Effects of the Nutraceutical Dehydrozingerone and Its CBiomolecules · 2024Article
- Ethnicity- and sex-specific genome wide association study on Parkinson's disease.NPJ Parkinson's disease · 2023Article
- LRRK2 Structure-Based Activation Mechanism and Pathogenesis.Biomolecules · 2023Review
- LRRK2 and Proteostasis in Parkinson's Disease.International journal of molecular sciences · 2022Review
- Reply to: Mild Chronic Colitis Triggers Parkinsonism in LRRK2 Mutant Mice through Activating TNF-α Pathway.Movement disorders : official journal of the Movement Disorder Society · 2022Article
- Genetic variations inFrontiers in neurology · 2022Review
- The Future of Genetic Disease Studies: Assembling an Updated Multidisciplinary Toolbox.Frontiers in cell and developmental biology · 2022Article
- Polygenic Risk Scores in a Prospective Parkinson's Disease Cohort.Movement disorders : official journal of the Movement Disorder Society · 2021Article
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13 authors.
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Abstract
Mutations in the Leucine-rich repeat kinase 2 gene (LRRK2) are associated with familial Parkinson's disease (PD). LRRK2 protein contains several functional domains, including protein-protein interaction domains at its N- and C-termini. In this study, we analyzed the functional features attributed to LRRK2 by its N- and C-terminal domains. We combined TIRF microscopy and synaptopHluorin assay to visualize synaptic vesicle trafficking. We found that N- and C-terminal domains have opposite impact on synaptic vesicle dynamics. Biochemical analysis demonstrated that different proteins are bound at the two extremities, namely β3-Cav2.1 at N-terminus part and β-Actin and Synapsin I at C-terminus domain. A sequence variant (G2385R) harboured within the C-terminal WD40 domain increases the risk for PD. Complementary biochemical and imaging approaches revealed that the G2385R variant alters strength and quality of LRRK2 interactions and increases fusion of synaptic vesicles. Our data suggest that the G2385R variant behaves like a loss-of-function mutation that mimics activity-driven events. Impaired scaffolding capabilities of mutant LRRK2 resulting in perturbed vesicular trafficking may arise as a common pathophysiological denominator through which different LRRK2 pathological mutations cause disease.
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