VPS35 – Parkinson disease

VPS35 encodes a core component of the retromer cargo‐recognition complex that mediates endosome-to-Golgi retrieval of membrane proteins. Heterozygous missense mutations in VPS35, most notably p.Asp620Asn, have been implicated in autosomal dominant, late-onset Parkinson disease ([PMID:21763483]). The clinical phenotype of VPS35-linked PD is largely indistinguishable from idiopathic PD, with typical tremor-predominant parkinsonism, bradykinesia, good levodopa response, and occasional cognitive impairment and depression.

Genetic analyses identified the p.Asp620Asn variant segregating with disease in an Austrian pedigree (23 probands; 16 affected, 7 alive carriers) and two additional families (5 and 10 affected members) in an autosomal dominant pattern with incomplete penetrance ([PMID:21763483]). A multicenter study of >15 000 individuals detected the same variant in 5 familial and 2 sporadic PD cases and not in controls, whereas other VPS35 variants (p.Leu774Met, p.Gly51Ser) showed no significant enrichment ([PMID:23125461]). Population screens confirm that p.Asp620Asn is rare (<0.3%) but reproducibly associated with PD across ethnicities.

Inheritance is autosomal dominant with incomplete penetrance. Segregation analysis demonstrates co-segregation of the variant with disease in 19 additional affected relatives beyond probands ([PMID:21763483]). To date, over 23 unrelated probands carry p.Asp620Asn, meeting ClinGen genetic evidence standards for a strong association.

Functional studies across model systems support a gain-of-function mechanism. Overexpression of D620N VPS35 in rat neurons induces cell death and heightened vulnerability to PD-related stressors ([PMID:24740878]). VPS35 D620N knock-in mice exhibit progressive nigrostriatal dopaminergic neuron loss, motor deficits, and synaptic pathology by 14 months ([PMID:30842285]). Drosophila expressing human D620N recapitulates age-dependent DA neuron loss and locomotor decline, whereas expression of nonpathogenic variants does not ([PMID:25288323]).

Mechanistic work reveals that D620N disrupts retromer association with the WASH complex, impairs endosome-to-Golgi retrieval of key receptors such as Lamp2a, and compromises autophagic degradation of α-synuclein ([PMID:26203154]). The mutation also enhances mitochondrial fragmentation via increased MUL1-mediated MFN2 degradation and triggers complex I/IV defects in patient fibroblasts ([PMID:26321632]). Moreover, D620N augments LRRK2 kinase–mediated Rab phosphorylation, suggesting epistatic interaction and potential for LRRK2 inhibitor therapy ([PMID:29743203]).

No convincing conflicting evidence has emerged; other VPS35 variants lack segregation or functional impact. Overall, the VPS35 D620N mutation has been robustly replicated, segregates in large families, and produces concordant functional phenotypes in multiple models, meeting criteria for a Strong gene-disease association.

Key Take-home: Testing for VPS35 p.Asp620Asn informs diagnosis of autosomal dominant Parkinson disease, guides genetic counseling for at-risk relatives, and identifies patients who may benefit from future retromer- or LRRK2-targeted therapies.

References

• American Journal of Human Genetics • 2011 • A mutation in VPS35, encoding a subunit of the retromer complex, causes late‐onset Parkinson disease. PMID:21763483
• Journal of Medical Genetics • 2012 • A multi-centre clinico-genetic analysis of the VPS35 gene in Parkinson disease indicates reduced penetrance for disease-associated variants. PMID:23125461
• Human Molecular Genetics • 2014 • In vivo evidence of pathogenicity of VPS35 mutations in the Drosophila. PMID:25288323
• Proceedings of the National Academy of Sciences of the United States of America • 2019 • Parkinson's disease-linked D620N VPS35 knockin mice manifest tau neuropathology and dopaminergic neurodegeneration. PMID:30842285
• Molecular Brain • 2014 • VPS35 mutations in Parkinson disease. PMID:24740878
• Cell Reports • 2015 • VPS35 deficiency or mutation causes dopaminergic neuronal loss by impairing mitochondrial fusion and function. PMID:26321632
• The Biochemical Journal • 2018 • The Parkinson's disease VPS35[D620N] mutation enhances LRRK2-mediated Rab protein phosphorylation in mouse and human. PMID:29743203
• The Journal of Neuroscience • 2015 • VPS35 in Dopamine Neurons Is Required for Endosome-to-Golgi Retrieval of Lamp2a, a Receptor of Chaperone-Mediated Autophagy That Is Critical for α-Synuclein Degradation and Prevention of Pathogenesis of Parkinson's Disease. PMID:26203154

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