ArticleScience signaling2021
Dysregulation of the AP2M1 phosphorylation cycle by LRRK2 impairs endocytosis and leads to dopaminergic neurodegeneration.
Article in Science signaling, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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Who cites it
26 citing papers in PubMed, 40 citations in OpenAlex.
- BAG3 modulates clathrin-mediated endocytosis and tau uptake in astrocytes.American journal of physiology. Cell physiology · 2026Article
- Role of LRRK2 in physiological activities, diseases, and therapy.Chinese medical journal · 2026Review
- Mendelian randomization analysis identifies HLA-A and AP2M1 as genetic biomarkers linked to immune-endocytic crosstalk in intervertebral disc degeneration.Journal of cell communication and signaling · 2026Article
- 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
- BAG3 modulates clathrin-mediated endocytosis and tau uptake in astrocytes.bioRxiv : the preprint server for biology · 2025Article
- Development of pyrazolo[1,5-a]pyrimidine based macrocyclic kinase inhibitors targeting AAK1.European journal of medicinal chemistry · 2025Article
- LRRK2 and the fragile synapse: a molecular prelude to Parkinson's disease?The Biochemical journal · 2025Review
- Copy Number Variation and SNP Affect Egg Production in Chickens by Regulating AP2M1 Expression to Inhibit GnRH Synthesis.Animals : an open access journal from MDPI · 2025Article
- SNX10 enhances HCoV-OC43 infection by facilitating viral entry and inhibiting virus-triggered autophagy.Virologica Sinica · 2025Article
- Tau uptake by human neurons depends on receptor LRP1 and kinase LRRK2.The EMBO journal · 2025Article
- LRRK2 in Drosophila Melanogaster Model: Insights into Cellular Dysfunction and Neuroinflammation in Parkinson's Disease.International journal of molecular sciences · 2025Review
- In-silico pharmacological insights into the therapeutic potential of microRNAs for microplastic-associated cancers.Frontiers in cell and developmental biology · 2025Review
- CalDAG-GEFI acts as a guanine nucleotide exchange factor for LRRK2 to regulate LRRK2 function and neurodegeneration.Science advances · 2024Article
- LRRK2 in Parkinson's disease: upstream regulation and therapeutic targeting.Trends in molecular medicine · 2024Review
- SUMOylation-induced membrane localization of TRPV1 suppresses proliferation and migration in gastric cancer cells.Cell communication and signaling : CCS · 2024Article
- Diverse Functions of Parkin in Midbrain Dopaminergic Neurons.Movement disorders : official journal of the Movement Disorder Society · 2024Review
- ELM-the Eukaryotic Linear Motif resource-2024 update.Nucleic acids research · 2024Article
- How Parkinson's Disease-Linked LRRK2 Mutations Affect Different CNS Cell Types.Journal of Parkinson's disease · 2024Review
- Regulation of LRRK2 mRNA stability by ATIC and its substrate AICAR through ARE-mediated mRNA decay in Parkinson's disease.The EMBO journal · 2023Article
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
Abstract
Mutations in the kinase LRRK2 and impaired endocytic trafficking are both implicated in the pathogenesis of Parkinson's disease (PD). Expression of the PD-associated LRRK2 mutant in mouse dopaminergic neurons was shown to disrupt clathrin-mediated endocytic trafficking. Here, we explored the molecular mechanism linking LRRK2 to endocytosis and found that LRRK2 bound to and phosphorylated the μ2 subunit of the adaptor protein AP2 (AP2M1), a core component of the clathrin-mediated endocytic machinery. Analysis of human SH-SY5Y cells and mouse neurons and tissues revealed that loss of LRRK2 abundance or kinase function resulted in decreased phosphorylation of AP2M1, which is required for the initial formation of clathrin-coated vesicles (CCVs). In contrast, overexpression of LRRK2 or expression of a Parkinson's disease-associated gain-of-function mutant LRRK2 (G2019S) inhibited the uncoating of AP2M1 from CCVs at later stages and prevented new cycles of CCV formation. Thus, the abundance and activity of LRRK2 must be calibrated to ensure proper endocytosis. Dysregulated phosphorylation of AP2M1 from the brain but not thyroid tissues of LRRK2 knockout and G2019S-knockin mice suggests a tissue-specific regulatory mechanism of endocytosis. Furthermore, we found that LRRK2-dependent phosphorylation of AP2M1 mediated dopaminergic neurodegeneration in a
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