DOPAMINE NEURONS FROM TRANSGENIC MICE WITH A KNOCKOUT OF THE P53 GENERESIST MPTP NEUROTOXICITY

We have examined MPTP toxicity to dopamine neurons of mice homozygous for a transgenic knockout of the p53 growth control gene (p53(-/-)). M PTP at a total dose of 96 mg/kg administered in four doses over two da ys produced a non-homogeneous loss of striatal dopamine transport site s and quantitatively reduced 3H-mazindol binding to similar degrees in p53(-/-) and wild type controls 2 and 3 weeks after starting MPTP. Ni gral DA neurons stained immunohistochemically for tyrosine hydroxylase were counted using both manual and automated methods and found to be reduced 29-34% in wild type controls but were not reduced in p53(-/-). Mean DA neuronal surface areas were reduced 63-68% by MPTP in control s and 35-50% in p53(-/-). We conclude that p53 protein appears necessa ry for complete expression of MPTP neurotoxicity to dopamine neurons. Our findings suggest that the p53 gene and other growth control genes may regulate dopamine neuronal death in PD. (C) 1996 Academic Press Li mited