ArticleMolecular neurodegeneration2016
LRRK2 phosphorylates pre-synaptic N-ethylmaleimide sensitive fusion (NSF) protein enhancing its ATPase activity and SNARE complex disassembling rate.
Article in Molecular neurodegeneration, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 63 papers.
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63 citing papers in PubMed, 185 citations in OpenAlex.
- Pharmacological Inhibition of Small Extracellular Vesicle Secretion by ALK5i SD-208 via Lysosomal Rerouting of CD63+ Compartments.Journal of extracellular vesicles · 2026Article
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- LRRK2 regulates ArfGAP1 membrane localization, activity and neuronal toxicity via phosphorylation within its lipid-sensing ALPS2 motif.bioRxiv : the preprint server for biology · 2026Article
- LRRK2 regulates ArfGAP1 membrane localization, activity and neuronal integrity via phosphorylation within its lipid-sensing ALPS2 motif.Frontiers in molecular neuroscience · 2026Article
- LRRK2 and the fragile synapse: a molecular prelude to Parkinson's disease?The Biochemical journal · 2025Review
- LRRK2 kinase modulates glucose-stimulated insulin secretion via RAB8 phosphorylation and ciliogenesis.Cellular and molecular life sciences : CMLS · 2025Article
- Role of LRRK2 in axonal transport and Parkinson's disease.The Biochemical journal · 2025Review
- Immune cell metabolic dysfunction in Parkinson's disease.Molecular neurodegeneration · 2025Review
- Characterisation of the function of a lncRNA containing SINE-VNTR-Alu 67 to regulate the genes at theExperimental biology and medicine (Maywood, N.J.) · 2025Article
- Genetic evidence for a functional association between Parkinson's disease proteins leucine-rich repeat kinase 2 andFrontiers in molecular neuroscience · 2025Article
- CalDAG-GEFI acts as a guanine nucleotide exchange factor for LRRK2 to regulate LRRK2 function and neurodegeneration.Science advances · 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
- The role of synaptic protein NSF in the development and progression of neurological diseases.Frontiers in neuroscience · 2024Review
- Cellular and subcellular localization of Rab10 and phospho-T73 Rab10 in the mouse and human brain.Acta neuropathologica communications · 2023Article
- Article
- Inhibition of the Exocyst Complex Attenuates the LRRK2 Pathological Effects.International journal of molecular sciences · 2023Article
- Impaired dopamine release in Parkinson's disease.Brain : a journal of neurology · 2023Review
- Impaired ATF3 signaling involves SNAP25 in SOD1 mutant ALS patients.Scientific reports · 2023Article
- Genetic overlap between cortical brain morphometry and frontotemporal dementia risk.Cerebral cortex (New York, N.Y. : 1991) · 2023Article
- Analysis ofBioMed research international · 2023Article
3 more citing papers are in PubMed but not listed here.
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16 authors at 3 institutions in 1 country.
Funding
Abstract
backgroundLrrk2, a gene linked to Parkinson's disease, encodes a large scaffolding protein with kinase and GTPase activities implicated in vesicle and cytoskeletal-related processes. At the presynaptic site, LRRK2 associates with synaptic vesicles through interaction with a panel of presynaptic proteins.
resultsHere, we show that LRRK2 kinase activity influences the dynamics of synaptic vesicle fusion. We therefore investigated whether LRRK2 phosphorylates component(s) of the exo/endocytosis machinery. We have previously observed that LRRK2 interacts with NSF, a hexameric AAA+ ATPase that couples ATP hydrolysis to the disassembling of SNARE proteins allowing them to enter another fusion cycle during synaptic exocytosis. Here, we demonstrate that NSF is a substrate of LRRK2 kinase activity. LRRK2 phosphorylates full-length NSF at threonine 645 in the ATP binding pocket of D2 domain. Functionally, NSF phosphorylated by LRRK2 displays enhanced ATPase activity and increased rate of SNARE complex disassembling. Substitution of threonine 645 with alanine abrogates LRRK2-mediated increased ATPase activity.
conclusionsGiven that the most common Parkinson's disease LRRK2 G2019S mutation displays increased kinase activity, our results suggest that mutant LRRK2 may impair synaptic vesicle dynamics via aberrant phosphorylation of NSF.
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