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Significance The neuropathological spectrum of Parkinson’s disease (PD) brains harboringVPS35 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. TheD620N VPS35 knockin mice provide an important new tool for distinguishing the neuropathological consequences and mechanisms of familialVPS35 mutations, including the intersection with other PD genetic risk factors.

Parkinson’s disease-linked D620N VPS35 knockin mice manifest tau neuropathology and dopaminergic neurodegeneration