GAPDH knockdown rescues mesencephalic dopaminergic neurons from MPP+-induced apoptosis

Glyceraldehyde-3-phosphate dehydrogenase (GAPDH; EC 1.2.1.12) has a number of diverse functions apart from glycolytic function. We explored the possible involvement of GAPDH in 1-methyl-4-phenylpyridinium (MPP)-induced death of mesencephalic dopaminergic neurons (MDNs) in culture. MPP (10 and 20 μM, 24 h) exposure selectively decreased the survival of tyrosine hydroxylase positive (TH) MDNs, which manifested apoptotic features including shrinkage of the cell body, chromatin condensation and nuclear fragmentation. Two types of GAPDH antisense oligonucleotides almost completely rescued MDNs from MPP toxicity. GAPDH was strongly expressed in apoptotic TH neurons, and MPP exposure significantly increased the percentage of TH neurons in which GAPDH is over-expressed. Confocal microscopic analysis demonstrated the nuclear accumulation of GAPDH in neurons undergoing MPP-induced apoptosis. These results suggest that MPP causes apoptosis of MDNs, concomitant with the over-expression and nuclear accumulation of GAPDH.