VPS35 and α-Synuclein fail to interact to modulate neurodegeneration in rodent models of Parkinson's disease

BackgroundMutations in the vacuolar protein sorting 35 ortholog (VPS35) gene cause late-onset, autosomal dominant Parkinson's disease (PD), with a single missense mutation (Asp620Asn, D620N) known to segregate with disease in families with PD. The VPS35 gene encodes a core component of the retromer complex, involved in the endosomal sorting and recycling of transmembrane cargo proteins. VPS35-linked PD is clinically indistinguishable from sporadic PD, although it is not yet known whether VPS35-PD brains exhibit & alpha;-synuclein-positive brainstem Lewy pathology that is characteristic of sporadic cases. Prior studies have suggested a functional interaction between VPS35 and the PD-linked gene product & alpha;-synuclein in lower organisms, where VPS35 deletion enhances & alpha;-synuclein-induced toxicity. In mice, VPS35 overexpression is reported to rescue hippocampal neuronal loss in human & alpha;-synuclein transgenic mice, potentially suggesting a retromer deficiency in these mice.MethodsHere, we employ multiple well-established genetic rodent models to explore a functional or pathological interaction between VPS35 and & alpha;-synuclein in vivo.ResultsWe find that endogenous & alpha;-synuclein is dispensable for nigrostriatal pathway dopaminergic neurodegeneration induced by the viral-mediated delivery of human D620N VPS35 in mice, suggesting that & alpha;-synuclein does not operate downstream of VPS35. We next evaluated retromer levels in affected brain regions from human A53T-& alpha;-synuclein transgenic mice, but find normal levels of the core subunits VPS35, VPS26 or VPS29. We further find that heterozygous VPS35 deletion fails to alter the lethal neurodegenerative phenotype of these A53T-& alpha;-synuclein transgenic mice, suggesting the absence of retromer deficiency in this PD model. Finally, we explored the neuroprotective capacity of increasing VPS35 expression in a viral-based human wild-type & alpha;-synuclein rat model of PD. However, we find that the overexpression of wild-type VPS35 is not sufficient for protection against & alpha;-synuclein-induced nigral dopaminergic neurodegeneration, & alpha;-synuclein pathology and reactive gliosis.ConclusionCollectively, our data suggest a limited interaction of VPS35 and & alpha;-synuclein in neurodegenerative models of PD, and do not provide support for their interaction within a common pathophysiological pathway.