The gene encoding vacuolar protein sorting protein 35 (VPS35) has been definitively linked to late onset familial PD following the identification of a point mutation (D620N) as the causal agent in a Swiss family.
Unexpectedly, endogenous D620N VPS35 expression induces robust tau-positive somatodendritic pathology throughout the brain as indicated by abnormal hyperphosphorylated and conformation-specific tau, which may represent an important and early feature of mutant VPS35-induced neurodegeneration in PD.
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.
Importantly, VPS35 D620N mutant-induced mitochondrial fragmentation and respiratory deficits could be rescued by the treatment of this decoy peptide in both M17 cells overexpressing D620N or PD fibroblasts bearing this mutation.
A hereditary Parkinson's-disease-causing point mutation (D620N) in the retromer subunit VPS35 perturbs retromer's association with the WASH complex and also with the uncharacterized protein ankyrin-repeat-domain-containing protein 50 (ANKRD50).
Identification of VPS35 p.D620N mutation-related Parkinson's disease in a Taiwanese family with successful bilateral subthalamic nucleus deep brain stimulation: a case report and literature review.
Here we demonstrate that PD-associated VPS35 mutations caused mitochondrial fragmentation and cell death in cultured neurons in vitro, in mouse substantia nigra neurons in vivo and in human fibroblasts from an individual with PD who has the VPS35(D620N) mutation.
More importantly, although the PD-associated VPS35 mutant VPS35 (D620N) still interacted with DRD1, its expression did not affect cell surface recycling of DRD1 and phosphorylation of CREB/ERK nor rescue the reduction of CREB/ERK phosphorylation caused by VPS35 downregulation.
These data define the primary molecular defect in retromer assembly that arises from the VPS35(D620N) mutation and, by revealing functional effects on retromer-mediated endosome-to-TGN transport, provide new insight into retromer deregulation in Parkinson disease.
In summary, we find that the expression of Vps35 D620N leads to endosomal alterations and trafficking defects that may partly explain its action in PD.
Recently, 2 studies identified the Asp620Asn mutation in the vacuolar protein sorting 35 (VPS35) gene, and the Arg1205His in the eukaryotic translation initiation factor 4 gamma 1 gene (EIF4G1) were reported to be associated an autosomal dominant form of PD.
Our study apart from identifying the p.Asp620Asn variant in familial cases also identified it in idiopathic Parkinson disease cases, and thus provides genetic evidence for a role of p.Asp620Asn in Parkinson disease in different populations worldwide.