Wld^S mice are protected against the Parkinsonian mimetic MPTP

The progressive loss of the nigrostriatal pathway is a distinguishing feature of Parkinson's disease. Because terminal field loss appears to precede cell body loss, we tested whether the mouse mutant Wld^S, which delays axonal degeneration in a variety of disorders, would ameliorate nigrostriatal degeneration following treatment with the Parkinsonian mimetic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The present findings show that the Wld^S gene product enhances survival, prevents nigrostriatal axon degeneration, and attenuates neurotransmitter loss but does not rescue cell bodies. As MPTP is thought to impair mitochondrial energy production, these data suggest that disease pathology due to metabolic dysfunction could be improved by the Wld^S gene product. These results suggest new therapeutic avenues for Parkinson's disease.