ArticleThe Journal of cell biology2024
RAB3 phosphorylation by pathogenic LRRK2 impairs trafficking of synaptic vesicle precursors.
Article in The Journal of cell biology, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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Who cites it
25 citing papers in PubMed, 23 citations in OpenAlex.
- Pathogenic KIF1A variants differentially disrupt axonal trafficking and impede synaptic development.The Journal of cell biology · 2026Article
- PPM1H loss alters intrasynaptic alpha-synuclein localization in a LRRK2-dependent manner.Molecular brain · 2026Article
- Article
- Leucine-rich repeat kinase 2 impairs the release sites of Parkinson's disease vulnerable dopamine axons.Nature communications · 2026Article
- Convergent transcriptomic signature in iPSC-dopaminergic neurons of hereditary Parkinson's disease.Life science alliance · 2026Article
- DYRK1A and Parkinson's disease, facts and hypotheses.Neurobiology of disease · 2026Review
- Axonal Transport Deficits in Parkinson's Disease: Insights from Neurotoxin, Genetic, and Sporadic Models.Brain sciences · 2026Review
- PINK1/Parkin-dependent mitophagy mediates astrocytic inflammatory responses to mitochondrial damage.bioRxiv : the preprint server for biology · 2026Article
- New insights into synaptic vesicle dysfunction in Parkinson's disease.Journal of Parkinson's disease · 2026Review
- Roles in physiology and disease of the inositol phosphatase synaptojanin 1.Biochimica et biophysica acta. Molecular and cell biology of lipids · 2026Review
- Pathogenic KIF1A variants differentially disrupt axonal trafficking and impede synaptic development.bioRxiv : the preprint server for biology · 2026Article
- RAB3A variants in ataxia and other neurodegenerative disorders.Brain : a journal of neurology · 2026Article
- Peripheral and CSF protein quantification in Parkinson's disease and multiple system atrophy-the nucleic acid-linked immuno-sandwich assay.Brain communications · 2026Article
- Article
- Formation, Organization, and Maintenance of Synaptic Vesicle Pools: From Molecules to Structure and Dynamics.Advances in neurobiology · 2026Review
- LRRK2 and the fragile synapse: a molecular prelude to Parkinson's disease?The Biochemical journal · 2025Review
- Soma-localized Rab39 inhibits synaptic autophagy by controlling trafficking of Atg9 vesicles.The EMBO journal · 2025Article
- Biogenesis and reformation of synaptic vesicles.The Journal of physiology · 2025Review
- Leucine-rich repeat kinase 2 impairs the release sites of Parkinson's disease vulnerable dopamine axons.bioRxiv : the preprint server for biology · 2025Article
- Deficiency of Rab26 causes behavioral defects in mice through impaired trafficking of serotonin (5-HT) transporter.iScience · 2025Article
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3 authors at 2 institutions in 1 country.
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Abstract
Gain-of-function mutations in the LRRK2 gene cause Parkinson's disease (PD), characterized by debilitating motor and non-motor symptoms. Increased phosphorylation of a subset of RAB GTPases by LRRK2 is implicated in PD pathogenesis. We find that increased phosphorylation of RAB3A, a cardinal synaptic vesicle precursor (SVP) protein, disrupts anterograde axonal transport of SVPs in iPSC-derived human neurons (iNeurons) expressing hyperactive LRRK2-p.R1441H. Knockout of the opposing protein phosphatase 1H (PPM1H) in iNeurons phenocopies this effect. In these models, the compartmental distribution of synaptic proteins is altered; synaptophysin and synaptobrevin-2 become sequestered in the neuronal soma with decreased delivery to presynaptic sites along the axon. We find that RAB3A phosphorylation disrupts binding to the motor adaptor MADD, potentially preventing the formation of the RAB3A-MADD-KIF1A/1Bβ complex driving anterograde SVP transport. RAB3A hyperphosphorylation also disrupts interactions with RAB3GAP and RAB-GDI1. Our results reveal a mechanism by which pathogenic hyperactive LRRK2 may contribute to the altered synaptic homeostasis associated with characteristic non-motor and cognitive manifestations of PD.
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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.