Akt1/PKBalpha protects PC12 cells against the parkinsonism-inducing neurotoxin 1-methyl-4-phenylpyridinium and reduces the levels of oxygen-free radicals.

The phosphatidylinositol (PI)-3 kinase-Akt/PKB survival pathway protects neurons from apoptosis caused by diverse stress stimuli. However, its protective effect against neurotoxins that produce oxidative stress and neurodegeneration has not been investigated. We analyzed the effect of this pathway on the action of the parkinsonism-inducing neurotoxin 1-methyl-4-phenylpyridinium (MPP+). Overexpression of a membrane-targeted, N-myristylated fusion protein of enhanced green fluorescence protein (EGFP) and mouse Akt1 attenuated the apoptotic effect of the neurotoxin in PC12 cells. This effect was not due to protection of mitochondrial complex I activity or restoration of energy charge. Following MPP+-treatment, myr-EGFP-Akt1-transfected cells exhibited an unaltered mitochondrial membrane potential and lower ROS levels than control cells. These results provide a new site of action of Akt/PKB at the level of the oxidative detoxifying cell machinery and suggest that this effect may be responsible in part for the resistance of myr-EGFP-Akt1-expressing cells to oxidative stress and MPP+-induced apoptosis.