ArticleHuman molecular genetics2018
Parkin mediates the ubiquitination of VPS35 and modulates retromer-dependent endosomal sorting.
Article in Human molecular genetics, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 49 papers.
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Who cites it
49 citing papers in PubMed, 75 citations in OpenAlex.
- Parkinson's disease-linked D620N mutation selectively alters the brain-specific protein interactome of VPS35.Neurobiology of disease · 2026Article
- Lysosomal dysfunction in neurodegenerative disease.Nature reviews. Neurology · 2026Review
- Parkinson's disease-associated LRRK2 risk variant, G2385R, enhances Rab substrate phosphorylation and impairs neuronal integrity.Human molecular genetics · 2026Article
- Retromer-targeted therapy for neurodegenerative diseases.Molecular neurodegeneration · 2026Review
- 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
- Ubiquitin ligase signalling networks shape presynaptic development, function and disease.The Journal of physiology · 2025Review
- Nuclear VPS35 attenuates NHEJ repair by sequestering Ku protein.Molecular medicine (Cambridge, Mass.) · 2025Article
- VPS35-Retromer: Multifunctional Roles in Various Biological Processes - A Focus on Neurodegenerative Diseases and Cancer.Journal of inflammation research · 2025Review
- Strategies for modeling aging and age-related diseases.npj aging · 2024Review
- Key genes and convergent pathogenic mechanisms in Parkinson disease.Nature reviews. Neuroscience · 2024Review
- VPS35 and retromer dysfunction in Parkinson's disease.Philosophical transactions of the Royal Society of London. Series B, Biological sciences · 2024Review
- Cell biology of Parkinson's disease: Mechanisms of synaptic, lysosomal, and mitochondrial dysfunction.Current opinion in neurobiology · 2024Review
- EhVps35, a retromer component, is a key factor in secretion, motility, and tissue invasion byFrontiers in cellular and infection microbiology · 2024Article
- VPS35 and α-Synuclein fail to interact to modulate neurodegeneration in rodent models of Parkinson's disease.Molecular neurodegeneration · 2023Article
- Ubiquitin and its relatives as wizards of the endolysosomal system.Journal of cell science · 2023Article
- Loss of NDR1/2 kinases impairs endomembrane trafficking and autophagy leading to neurodegeneration.Life science alliance · 2023Article
- Receptor Recycling by Retromer.Molecular and cellular biology · 2023Review
- Cell Biology of Parkin: Clues to the Development of New Therapeutics for Parkinson's Disease.CNS drugs · 2022Review
- Mitochondrial membrane proteins and VPS35 orchestrate selective removal of mtDNA.Nature communications · 2022Article
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Authors and funding
6 authors at 3 institutions in 2 countries.
Funding
Abstract
Mutations in a number of genes cause familial forms of Parkinson's disease (PD), including mutations in the vacuolar protein sorting 35 ortholog (VPS35) and parkin genes. In this study, we identify a novel functional interaction between parkin and VPS35. We demonstrate that parkin interacts with and robustly ubiquitinates VPS35 in human neural cells. Familial parkin mutations are impaired in their ability to ubiquitinate VPS35. Parkin mediates the attachment of an atypical poly-ubiquitin chain to VPS35 with three lysine residues identified within the C-terminal region of VPS35 that are covalently modified by ubiquitin. Notably, parkin-mediated VPS35 ubiquitination does not promote the proteasomal degradation of VPS35. Furthermore, parkin does not influence the steady-state levels or turnover of VPS35 in neural cells and VPS35 levels are normal in the brains of parkin knockout mice. These data suggest that ubiquitination of VPS35 by parkin may instead serve a non-degradative cellular function potentially by regulating retromer-dependent sorting. Accordingly, we find that components of the retromer-associated WASH complex are markedly decreased in the brain of parkin knockout mice, suggesting that parkin may modulate WASH complex-dependent retromer sorting. Parkin gene silencing in primary cortical neurons selectively disrupts the vesicular sorting of the autophagy receptor ATG9A, a WASH-dependent retromer cargo. Parkin is not required for dopaminergic neurodegeneration induced by the expression of PD-linked D620N VPS35 in mice, consistent with VPS35 being located downstream of parkin function. Our data reveal a novel functional interaction of parkin with VPS35 that may be important for retromer-mediated endosomal sorting and PD.
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