ArticleHuman molecular genetics2015
VPS35 pathogenic mutations confer no dominant toxicity but partial loss of function in Drosophila and genetically interact with parkin.
Article in Human molecular genetics, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 45 papers.
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Who cites it
45 citing papers in PubMed, 86 citations in OpenAlex.
- Retromer-targeted therapy for neurodegenerative diseases.Molecular neurodegeneration · 2026Review
- VPS35 mutation inhibits PINK1/parkin-mediated mitophagy via increased LRRK2 kinase activity.Brain : a journal of neurology · 2026Article
- Article
- Strategies for modeling aging and age-related diseases.npj aging · 2024Review
- VPS35 and retromer dysfunction in Parkinson's disease.Philosophical transactions of the Royal Society of London. Series B, Biological sciences · 2024Review
- FBXO7/ntc and USP30 antagonistically set the ubiquitination threshold for basal mitophagy and provide a target for Pink1 phosphorylation in vivo.PLoS biology · 2023Article
- Sphingolipids in neurodegenerative diseases.Frontiers in neuroscience · 2023Review
- Understanding the contributions of VPS35 and the retromer in neurodegenerative disease.Neurobiology of disease · 2022Review
- Beware of Misdelivery: Multifaceted Role of Retromer Transport in Neurodegenerative Diseases.Frontiers in aging neuroscience · 2022Review
- Opposing functions for retromer and Rab11 in extracellular vesicle traffic at presynaptic terminals.The Journal of cell biology · 2021Article
- Sorting Out Sorting Nexins Functions in the Nervous System in Health and Disease.Molecular neurobiology · 2021Review
- Mitochondrial function in development and disease.Disease models & mechanisms · 2021Review
- The cell biology of Parkinson's disease.The Journal of cell biology · 2021Review
- The Importance ofCells · 2021Review
- The Role of VPS35 in the Pathobiology of Parkinson's Disease.Cellular and molecular neurobiology · 2021Review
- Mechanisms ofInternational review of movement disorders · 2021Article
- Review
- Tollip coordinates Parkin-dependent trafficking of mitochondrial-derived vesicles.The EMBO journal · 2020Article
- Article
- Autophagy in Parkinson's Disease.Journal of molecular biology · 2020Review
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
Mutations in VPS35 (PARK17) cause autosomal dominant, late onset Parkinson's disease (PD). VPS35 forms a core component of the retromer complex that mediates the retrieval of membrane proteins from endosomes back to either the Golgi or plasma membrane. While aberrant endosomal protein sorting has been linked to several neurodegenerative diseases, the mechanisms by which VPS35 mutations and retromer function contribute to PD pathogenesis are not clear. To address this, we generated transgenic Drosophila that express variant forms of human VPS35 found in PD cases and the corresponding variants of the Drosophila ortholog. We did not find evidence of dominant toxicity from any variant form including the pathogenic D620N mutation, even with aging. However, assessing the ability of Vps35 variants to rescue multiple vps35-mutant phenotypes, we found that the D620N mutation confers a partial loss of function. Recently, VPS35 has been linked to the formation of mitochondria-derived vesicles, which mediate the degradation of mitochondrial proteins and contribute to mitochondrial quality control. This process is also promoted by two other PD-lined genes parkin (PARK2) and PINK1 (PARK6). We demonstrate here that vps35 genetically interacts with parkin but interestingly not with pink1. Strikingly, Vps35 overexpression is able to rescue several parkin-mutant phenotypes. Together these findings provide in vivo evidence that the D620N mutation likely confers pathogenicity through a partial loss of function mechanism and that this may be linked to other known pathogenic mechanisms such as mitochondrial dysfunction.
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