α-Synuclein is a major component of Lewy bodies, neuronal inclusions diagnostic for Parkinson’s disease (PD). While an Ala53Thr mutation in α-synuclein can cause PD in humans, in mice the wildtype residue at position 53 is threonine, indicating that mice are either too short-lived to develop PD, or are protected by the six other amino acid differences between the proteins in these two species. Mice carrying an Ala53Thr human SNCA transgene driven by the mouse prion promoter show a mild movement disorder and only rarely develop severe pathology by 2 years of age. To determine whether the presence of mouse α-synuclein affects the pathogenicity of the human protein, the transgene was crossed into mice lacking endogenous α-synuclein. Mice that express only human α-synuclein developed a neuronopathy characterized by limb weakness and paralysis with onset beginning at 16 months of age. The neuronopathy is probably due to high levels of expression of the transgene in the ventral spinal cord leading to motor neuron damage and Wallerian degeneration of the ventral roots. These data suggest mouse α-synuclein is protective against the deleterious effects of the human mutant protein.