The VPS35-D620N mutation is associated with Parkinson's disease and can be a target for gene therapy

There is evidence that the VPS35 protein impacts degradation of dopaminergic (DA) neuron lifespan and that the D620N mutation is associated with a kind of Parkinson's disease (PD) mimicking idiopathic PD. The incidence of this mutation and the likely pathogenic effects of additional VPS35 variants is unclear. Other unusual VPS35 mutations may put people at risk for Parkinson's disease, but the level of risk has yet to be determined.Due to the functional and genetic links between VPS35 and other PD-associated genes, rare VPS35 variants may be a key extra component in developing the PD phenotype in people with other mutations with inadequate penetration. Genetic association analysis could remedy this issue in the near future.VPS35-associated PD neuropathology is another significant aspect. Since just one D620N mutant carrier has been studied at autopsy to date, limited information is available about the neuropathological spectrum of PD patients with VPS35 mutations. It is yet unknown if neuronal loss in VPS35-related PD occurs just in SNc or affects other brain areas such as locus coeruleus, cortex, hippocampus and other structures. Neuropathology of VPS35-D620N mice models demonstrated severe tau pathology and axonal degradation, but no evidence of SYN inclusions. It's uncertain if PD individuals with VPS35 mutations have the same features.More study on the role of VPS35 in enhancing DA neuron survival is also needed to better understand the metabolic pathways damaged by VPS35 mutations and identify new therapy goals. The D620N VPS35 KI model, paired with the parkinQ311X mouse model, is one of the first monogenic PD models to recapitulate the fundamental PD feature: DA neuronal breakdown in SNc. These mouse models can be used to identify and assess drug targets. Because the neurodegenerative molecular pathways in many types of Parkinson's disease are so similar, drugs that confer neuroprotection in VPS35 models could be studied in other, more common types of Parkinson's disease.