INCREASED SUPEROXIDE-DISMUTASE ACTIVITY IMPROVES SURVIVAL OF CULTUREDPOSTNATAL MIDBRAIN NEURONS

Copper/zinc superoxide dismutase (Cu/Zn-SOD) is a major free radical s cavenging enzyme. Increased Cu/Zn-SOD activity protects cells against oxidative stress mediated by different mechanisms. However, there is a lso in vitro and in vivo evidence that, in the absence of abnormal oxi dative stress, chronic increased Cu/Zn-SOD activity is detrimental to living cells. To address this issue, we examined the fate of mature mi dbrain neurons from transgenic mice expressing human Cu/Zn-SOD and fro m their nontransgenic littermates. Midbrain from transgenic pups had a bout threefold higher Cu/Zn-SOD activity than that from nontransgenic pups. Virtually all transgenic neurons were strongly immunoreactive fo r human Cu/Zn-SOD protein in their cell bodies and processes. The numb er of midbrain neurons decreased over time in both transgenic and nont ransgenic cultures, but to a significantly smaller extent in the trans genic cultures. Postnatal midbrain neurons died by either necrosis or apoptosis, and increased Cu/Zn-SOD activity attenuated both forms of c ell death. Furthermore, increased Cu/Zn-SOD activity better prevented the loss of dopaminergic neurons than GABAergic neurons. We also found that neuronal processes were dramatically denser in transgenic cultur es than in nontransgenic cultures, These results indicate that chronic increased Cu/Zn-SOD activity does not appear to be detrimental, but r ather promotes cell survival and neuronal process development in postn atal midbrain neurons, probably by providing more efficient detoxifica tion of free radicals. They also show that increased Cu/Zn-SOD activit y does not seem to play a critical role in determining the mode of cel l death in this culture system.