Mice deficient in group IV cytosolic phospholipase A2 are resistant to MPTP neurotoxicity

Phospholipase A, (PLA,) enzymes are critical regulators of prostaglandin and leukotriene synthesis, and they may also play an important role in the generation of intracellular free radicals. The group IV cytosolic form of phospholipase A, (cPLA(2)) is regulated by changes in intracellular calcium concentration, and the enzyme preferentially acts to release arachidonic acid esterified at the sn-2 position of phospholipids. We examined the susceptibility of mice carrying a targeted mutation of the cPLA(2) gene to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity. Mutant mice have no functional cPLA2 activity. Mice that were homozygous for the mutation (cPLA(2)(-/-)) were significantly resistant to MPTP-induced dopamine depletion as compared 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 development of Parkinson's disease in humans.