GENETIC ELEVATION OF MONOAMINE-OXIDASE LEVELS IN DOPAMINERGIC PC12 CELLS RESULTS IN INCREASED FREE-RADICAL DAMAGE AND SENSITIVITY TO MPTP

Production of hydrogen peroxide as a by-product of the breakdown of ca techolamines by the enzyme monoamine oxidase (MAO) has been hypothesiz ed to contribute to the increased proclivity of dopaminergic neurons f or oxidative injury. We established clonal dopaminergic PC12 cell line s which have elevated MAO activity levels resulting from transgenic ex pression of the B isoform of the enzyme. Both MAO-A and MAO-B have rel atively equivalent affinities for dopamine, and since PC12 primarily e xpress the A and not the B form of the enzyme, this allowed us to dist inguish the transgenic MAO activity in these cells from endogenous usi ng the MAO-B specific substrate PEA. Elevation of MAO activity levels in the MAO-B + cells resulted in higher levels of both free radicals a nd free radical damage compared with controls. In addition, increased MAO-B levels within PC12 cells caused a dose-dependent increase in sen sitivity to the toxin MPTP. Our data suggests that oxidation of catech olamines by MAO can contribute to free radical damage in catecholamine rgic neurons and that the low MAO-B activity levels found endogenously in these cells likely accounts for their relative resistance to MPTP toxicity. (C) 1996 Wiley-Liss, Inc.