Dysregulation of the AP2M1 phosphorylation cycle by LRRK2 impairs endocytosis and leads to dopaminergic neurodegeneration
| Autor: | Yulan Xiong, Qinfang Liu, Daniel A. Higgins, Jianzhong Yu, Judith Bautista-Gomez |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Dopamine Endocytic cycle Endocytosis Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 Biochemistry Article 03 medical and health sciences Mice 0302 clinical medicine medicine Animals Phosphorylation Molecular Biology Kinase Chemistry Dopaminergic Neurons Neurodegeneration Dopaminergic Signal transducing adaptor protein Cell Biology medicine.disease LRRK2 Cell biology nervous system diseases 030104 developmental biology Mutation 030217 neurology & neurosurgery |
| Zdroj: | Sci Signal |
| ISSN: | 1937-9145 |
| Popis: | 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 µ1 subunit of the adaptor protein AP2 (AP2M1), a core component of the clathrin-mediated endocytic machinery. Analysis of human SH-SY5Y cells and mouse hippocampal 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 Drosophila model of PD. Together, our findings provide a mechanistic link between LRRK2, AP2, and endocytosis in the pathogenesis of PD. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|