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 possib le involvement of GAPDH in 1-methyl-4-phenylpyridinium (MPP+)-induced death of mesencephalic dopaminergic neurons (MDNs) in culture, MPP+ (10 and 20 m uM, 24 h) exposure selectively decreased the survival of tyrosine hydroxyla se positive (TH+) MDNs, which manifested apoptotic features including shrin kage of the fell body, chromatin condensation and nuclear fragmentation. Tw o 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 t he nuclear accumulation of GAPDH in neurons undergoing MPP+-induced apoptos is. These results suggest that MPP+ causes apoptosis of MDNs, concomitant w ith the overexpression and nuclear accumulation of GAPDH. NeuroReport 12:20 49-2052 (C) 2001 Lippincott Williams & Wilkins.