ArticleAging cell2021
VPS35 D620N knockin mice recapitulate cardinal features of Parkinson's disease.
Article in Aging cell, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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Who cites it
27 citing papers in PubMed, 49 citations in OpenAlex.
- CRISPR/Cas9-based nanodelivery systems for precision gene editing in neuroinflammation.Inflammation research : official journal of the European Histamine Research Society ... [et al.] · 2026Review
- Article
- VPS35 mutation inhibits PINK1/parkin-mediated mitophagy via increased LRRK2 kinase activity.Brain : a journal of neurology · 2026Article
- Strategies for Optimizing Genetic Mouse Models to Enhance the Understanding of Parkinson's Disease.Biomedicines · 2026Review
- Vps35 p. D620N causes Lrrk2 kinase hyperactivity, chronic microglial activation and inflammation.bioRxiv : the preprint server for biology · 2026Article
- Context-dependent ATP7 Interactions with Parkinson's Disease-associated Genes Modulate Copper Homeostasis Phenotypes.bioRxiv : the preprint server for biology · 2026Article
- Parkinson's Disease: The Epidemiology, Risk Factors, Molecular Pathogenesis, Prevention, and Therapy.MedComm · 2025Review
- Intranasal AβJournal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology · 2025Article
- Deficient AMPK-SENP1-Sirt3 signaling impairs mitochondrial complex I function in Parkinson's disease model.Translational neurodegeneration · 2025Article
- LRRK2-mediated mitochondrial dysfunction in Parkinson's disease.The Biochemical journal · 2025Review
- Emergent glutamate & dopamine dysfunction in VPS35NPJ Parkinson's disease · 2025Article
- Immune cell metabolic dysfunction in Parkinson's disease.Molecular neurodegeneration · 2025Review
- Endosomal traffic disorders: a driving force behind neurodegenerative diseases.Translational neurodegeneration · 2024Review
- The regulation of NFKB1 on CD200R1 expression and their potential roles in Parkinson's disease.Journal of neuroinflammation · 2024Article
- VPS35 or retromer as a potential target for neurodegenerative disorders: barriers to progress.Expert opinion on therapeutic targets · 2024Review
- Retromer-dependent lysosomal stress in Parkinson's disease.Philosophical transactions of the Royal Society of London. Series B, Biological sciences · 2024Review
- Inhibition of LRRK2 kinase activity rescues deficits in striatal dopamine physiology in VPS35 p.D620N knock-in mice.NPJ Parkinson's disease · 2023Article
- VPS35 and α-Synuclein fail to interact to modulate neurodegeneration in rodent models of Parkinson's disease.Molecular neurodegeneration · 2023Article
- Article
- Review
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Authors and funding
9 authors at 2 institutions in 2 countries.
Funding
Abstract
D620N mutation in the vacuolar protein sorting 35 ortholog (VPS35) gene causes late-onset, autosomal dominant familial Parkinson's disease (PD) and contributes to idiopathic PD. However, how D620N mutation leads to PD-related deficits in vivo remains unclear. In the present study, we thoroughly characterized the biochemical, pathological, and behavioral changes of a VPS35 D620N knockin (KI) mouse model with chronic aging. We reported that this VPS35 D620N KI model recapitulated a spectrum of cardinal features of PD at 14 months of age which included age-dependent progressive motor deficits, significant changes in the levels of dopamine (DA) and DA metabolites in the striatum, and robust neurodegeneration of the DA neurons in the SNpc and DA terminals in the striatum, accompanied by increased neuroinflammation, and accumulation and aggregation of α-synuclein in DA neurons. Mechanistically, D620N mutation induced mitochondrial fragmentation and dysfunction in aged mice likely through enhanced VPS35-DLP1 interaction and increased turnover of mitochondrial DLP1 complexes in vivo. Finally, the VPS35 D620N KI mice displayed greater susceptibility to MPTP-mediated degeneration of nigrostriatal pathway, indicating that VPS35 D620N mutation increased vulnerability of DA neurons to environmental toxins. Overall, this VPS35 D620N KI mouse model provides a powerful tool for future disease modeling and pharmacological studies of PD. Our data support the involvement of VPS35 in the development of α-synuclein pathology in vivo and revealed the important role of mitochondrial fragmentation/dysfunction in the pathogenesis of VPS35 D620N mutation-associated PD in vivo.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.