MICE DEFICIENT IN GROUP IV CYTOSOLIC PHOSPHOLIPASE A(2) ARE RESISTANTTO MPTP NEUROTOXICITY

Phospholipase A, (PLA,) enzymes are critical regulators of prostagland in and leukotriene synthesis, and they may also play an important role in the generation of intracellular free radicals. The group IV cytoso lic form of phospholipase A, (cPLA(2)) is regulated by changes in intr acellular calcium concentration, and the enzyme preferentially acts to release arachidonic acid esterified at the sn-2 position of phospholi pids. We examined the susceptibility of mice carrying a targeted mutat ion of the cPLA(2) gene to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridin e (MPTP)-induced neurotoxicity. Mutant mice have no functional cPLA2 a ctivity. Mice that were homozygous for the mutation (cPLA(2)(-/-)) wer e significantly resistant to MPTP-induced dopamine depletion as compar ed with littermate control (cPLA(2)(-/-)) and heterozygous mice (cPLA( 2)(+/-)). These findings provide evidence that cPLA(2) plays a role in MPTP neurotoxicity and suggest that cPLA(2) may play a role in the de velopment of Parkinson's disease in humans.