ArticleNeurobiology of disease2020
Sequential screening nominates the Parkinson's disease associated kinase LRRK2 as a regulator of Clathrin-mediated endocytosis.
Article in Neurobiology of disease, 2020. 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, 44 citations in OpenAlex.
- Leucine-rich repeat kinase 2 (LRRK2): balancing cellular homeostasis and Parkinson's disease (PD) pathogenesis.Annals of medicine · 2026Review
- Clathrin-mediated endocytosis as an axis for the etiopathogenesis of Parkinson's disease.Journal of cell science · 2026Review
- AP2: an indispensable host factor in virus infection.Journal of virology · 2026Review
- Traumatic Brain Injury and Endocytosis: Reduced Rodent Hippocampal Endocytosis Proteins and Human Clathrin Light Chain Polymorphisms Are Associated with Impaired Neurological Outcomes After TBI.Molecular neurobiology · 2026Article
- De novo variant analysis of childhood-onset obsessive-compulsive disorder in the French-Canadian population.Translational psychiatry · 2025Article
- Synergistic blood-based diagnostic value of AP3B1 and BMPR2 in Parkinson's disease.NPJ Parkinson's disease · 2025Article
- Tau uptake by human neurons depends on receptor LRP1 and kinase LRRK2.The EMBO journal · 2025Article
- Low-frequency genetic variants in GAK enhance Golgi function and protect against Parkinson's disease.medRxiv : the preprint server for health sciences · 2025Article
- Role of LRRK2 in axonal transport and Parkinson's disease.The Biochemical journal · 2025Review
- LRRK2 in Drosophila Melanogaster Model: Insights into Cellular Dysfunction and Neuroinflammation in Parkinson's Disease.International journal of molecular sciences · 2025Review
- Diverse Functions of Parkin in Midbrain Dopaminergic Neurons.Movement disorders : official journal of the Movement Disorder Society · 2024Review
- Dysregulation of SNX1-retromer axis in pharmacogenetic models of Parkinson's disease.Cell death discovery · 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
- LRK-1/LRRK2 and AP-3 regulate trafficking of synaptic vesicle precursors through active zone protein SYD-2/Liprin-α.PLoS genetics · 2024Article
- Cellular and subcellular localization of Rab10 and phospho-T73 Rab10 in the mouse and human brain.Acta neuropathologica communications · 2023Article
- Leucine-rich repeat kinase 2 at a glance.Journal of cell science · 2023Article
- Regulators of proteostasis are translationally repressed in fibroblasts from patients with sporadic and LRRK2-G2019S Parkinson's disease.NPJ Parkinson's disease · 2023Article
- LRRK2 recruitment, activity, and function in organelles.The FEBS journal · 2022Review
- Proteomics analysis of the p.G849D variant in neurexin 2 alpha may reveal insight into Parkinson's disease pathobiology.Frontiers in aging neuroscience · 2022Article
- Mutations in LRRK2 linked to Parkinson disease sequester Rab8a to damaged lysosomes and regulate transferrin-mediated iron uptake in microglia.PLoS biology · 2021Article
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Authors and funding
12 authors at 3 institutions in 2 countries.
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Abstract
Mutations in leucine-rich repeat kinase 2 (LRRK2) are an established cause of inherited Parkinson's disease (PD). LRRK2 is expressed in both neurons and glia in the central nervous system, but its physiological function(s) in each of these cell types is uncertain. Through sequential screens, we report a functional interaction between LRRK2 and Clathrin adaptor protein complex 2 (AP2). Analysis of LRRK2 KO tissue revealed a significant dysregulation of AP2 complex components, suggesting LRRK2 may act upstream of AP2. In line with this hypothesis, expression of LRRK2 was found to modify recruitment and phosphorylation of AP2. Furthermore, expression of LRRK2 containing the R1441C pathogenic mutation resulted in impaired clathrin-mediated endocytosis (CME). A decrease in activity-dependent synaptic vesicle endocytosis was also observed in neurons harboring an endogenous R1441C LRRK2 mutation. Alongside LRRK2, several PD-associated genes intersect with membrane-trafficking pathways. To investigate the genetic association between Clathrin-trafficking and PD, we used polygenetic risk profiling from IPDGC genome wide association studies (GWAS) datasets. Clathrin-dependent endocytosis genes were found to be associated with PD across multiple cohorts, suggesting common variants at these loci represent a cumulative risk factor for disease. Taken together, these findings suggest CME is a LRRK2-mediated, PD relevant pathway.
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