6 March 2019
The neuropathological spectrum of Parkinson’s disease (PD) brains harboring VPS35 mutations is not yet clear since only a single mutation carrier has been evaluated at autopsy. D620N VPS35 knockin mice developed here represent one of the first models of inherited PD that develop the robust and progressive degeneration of nigral dopaminergic neurons. Furthermore, these mice develop robust and widespread tau-positive pathology and axonal damage but lack signs of Lewy pathology positive for α-synuclein. VPS35 knockin mice indicate that the D620N mutation is sufficient for the development of tau abnormalities but not α-synuclein. The D620N VPS35 knockin mice provide an important new tool for distinguishing the neuropathological consequences and mechanisms of familial VPS35 mutations, including the intersection with other PD genetic risk factors.
Mutations in the vacuolar protein sorting 35 ortholog ( VPS35) gene represent a cause of late-onset, autosomal dominant familial Parkinson’s disease (PD). A single missense mutation, D620N, is considered pathogenic based upon its segregation with disease in multiple families with PD. At present, the mechanism(s) by which familial VPS35 mutations precipitate neurodegeneration in PD are poorly understood. Here, we employ a germline D620N VPS35 knockin (KI) mouse model of PD to formally establish the age-related pathogenic effects of the D620N mutation at physiological expression levels. Our data demonstrate that a heterozygous or homozygous D620N mutation is sufficient to reproduce key neuropathological hallmarks of PD as indicated by the progressive degeneration of nigrostriatal pathway dopaminergic neurons and widespread axonal pathology. 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. In contrast, we find no evidence for α-synuclein–positive neuropathology in aged VPS35 KI mice, a hallmark of Lewy body pathology in PD. D620N VPS35 expression also fails to modify the lethal neurodegenerative phenotype of human A53T-α-synuclein transgenic mice. Finally, by crossing VPS35 KI and null mice, our data demonstrate that a single D620N VPS35 allele is sufficient for survival and early maintenance of dopaminergic neurons, indicating that the D620N VPS35 protein is fully functional. Our data raise the tantalizing possibility of a pathogenic interplay between mutant VPS35 and tau for inducing neurodegeneration in PD.