Parkinsons disease(PD)is the most common neurodegenerative disorder affecting the motor system.It is characterized clinically by bradykinesia and resting tremor,and pathologically by dopaminergic neurodegeneration and intracellular Lewy body deposition.VPS35(vacuolar protein sorting 35)is a major component of the retromer complex that is essential for endosome-to-Golgi retrieval of membrane proteins.Mutations in the Vps35 gene have been identified in patients with autosomal dominant PD.However,how Vps35-mutation contributes to PD pathogenesis remains largely unknown.Here we provide evidence that links Vps35-deficiency to PD-relevant neuropathology.VPS35 was expressed in mouse dopamine(DA)neurons in substantianigra pars compacta(SNpc) and striatum,regions that are PD-vulnerable.Aged Vps35-deficient mice exhibited PD-like deficits including loss of DA transmitter in these areas and accumulation of ?-synuclein in SNpc-DA neurons.Remarkably,mitochondria were mal-functional in the midbrain of Vps35-deficient mice and fragmented in Vps35-deficient neurons.The mitochondrial fragmentation was restored by expression of wild type Vps35,but not PD-linked Vps35 mutant.Expression of PD-linked Vps35 mutants also fragmented mitochondria and decreased its membrane potential.Taken together,these results demonstrate an essential role for VPS35 in suppression of PD neuropathogenesis,providing a cellular mechanism for VPS35 dysfunction in mitochondrial impairment and PD pathogenesis.