Transfection-enforced Bcl-2 overexpression and an anti-Parkinson drug, rasagiline, prevent nuclear accumulation of glyceraldehyde-3-phosphate dehydrogenase induced by an endogenous dopaminergic neurotoxin, N-methyl(R)salsolinol

An endogenous dopaminergic neurotoxin, N-methyl(R)salsolinol, was found to induce apoptosis in human dopaminergic SH-SY5Y cells by step-wise activatio n of apoptotic cascade; collapse in mitochondrial membrane potential, Delta Psim, activation of caspases, and fragmentation of DNA. Recently, accumula tion of gylceraldehyde-3-phosphate dehydrogenase (GAPDH) in nuclei was prop osed to play an important role in apoptosis. In this paper, involvement of GAPDH in apoptosis induced by N-methyl(R)salsolinol was studied. The isoqui noline reduced Delta Psim within 3 h, as detected by a fluorescence indicat or, JC-1, then after 16 h incubation, GAPDH accumulated in nuclei by detect ion with immunostaining. To clarify the role of GAPDH in apoptotic process, a stable cell line of Bcl-2 overexpressed SH-SY5Y cells was established. O verexpression of Bcl-2 prevented the decline in Delta Psim and also apoptot ic DNA damage induced by N-methyl(R)salsolinol. In Bcl-2 transfected cells, nuclear translocation of GAPDH was also completely suppressed. In addition , a novel antiparkinsonian drug, rasagiline, prevented nuclear accumulation of GAPDH induced by N-methyl(R)salsolinol in control cells. These results suggest that GAPDH may accumulate in nuclei as a consequence of signal tran sduction, which is antagonized by anti-apoptotic Bcl-2 protein family and r asagiline. The results are discussed in concern to intracellular mechanism underlying anti-apoptotic function of rasagiline analogues.