ArticleScientific reports2020
The LRRK2 N-terminal domain influences vesicle trafficking: impact of the E193K variant.
Article in Scientific reports, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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Who cites it
10 citing papers in PubMed, 15 citations in OpenAlex.
- Leucine-rich repeat kinase 2 (LRRK2): balancing cellular homeostasis and Parkinson's disease (PD) pathogenesis.Annals of medicine · 2026Review
- The E193K LRRK2 mutation interferes with the autophagosome processing through the impairment of the LRRK2-Dynein-1 complex.Scientific reports · 2025Article
- LRRK2 kinase modulates glucose-stimulated insulin secretion via RAB8 phosphorylation and ciliogenesis.Cellular and molecular life sciences : CMLS · 2025Article
- A new LRRK2 variant in a family with Parkinson's disease affects binding to RAB8A.NPJ Parkinson's disease · 2025Article
- The significance of electrical signals in maturing spermatozoa for phosphoinositide regulation through voltage-sensing phosphatase.Nature communications · 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
- LRRK2 Structure-Based Activation Mechanism and Pathogenesis.Biomolecules · 2023Review
- Using single-vesicle technologies to unravel the heterogeneity of extracellular vesicles.Nature protocols · 2021Review
- Conformation and dynamics of the kinase domain drive subcellular location and activation of LRRK2.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
- A Critical LRRK at the Synapse? The Neurobiological Function and Pathophysiological Dysfunction of LRRK2.Frontiers in molecular neuroscience · 2020Review
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Authors and funding
11 authors at 5 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The LRRK2 protein consists of multiple functional domains, including protein-binding domains at its N and C-terminus. Mutations in the Leucine-rich repeat kinase 2 gene (LRRK2) have been linked to familial and sporadic Parkinson's disease (PD). We have recently described a novel variant falling within the N-terminal armadillo repeats, E193K. Herein, our aim is to investigate the functional impact of LRRK2 N-terminal domain and the E193K variant on vesicle trafficking. By combining Total Internal Reflection Fluorescence (TIRF) microscopy and a synaptopHluorin assay, we found that expression of a construct lacking the N-terminal domain increases the frequency and amplitude of spontaneous synaptic events. Complementary biochemical approaches showed that the E193K variant alters the binding properties of LRRK2, decreases LRRK2 binding to synaptic vesicles, and promotes vesicle fusion. Our results confirm the physiological and pathological relevance of the nature of the LRRK2-associated macro-molecular complex solidifying the idea that different pathological mutations critically alter the scaffolding function of LRRK2 resulting in a perturbation of the vesicular trafficking as a common denominator.
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