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 activation of apoptotic cascade; collapse in mitochondrial membrane potential, DeltaPsim, activation of caspases, and fragmentation of DNA. Recently, accumulation of gylceraldehyde-3-phosphate dehydrogenase (GAPDH) in nuclei was proposed to play an important role in apoptosis. In this paper, involvement of GAPDH in apoptosis induced by N-methyl(R)salsolinol was studied. The isoquinoline reduced DeltaPsim within 3 h, as detected by a fluorescence indicator, JC-1, then after 16 h incubation, GAPDH accumulated in nuclei by detection with immunostaining. To clarify the role of GAPDH in apoptotic process, a stable cell line of Bcl-2 overexpressed SH-SY5Y cells was established. Overexpression of Bcl-2 prevented the decline in DeltaPsim and also apoptotic 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 transduction, which is antagonized by anti-apoptotic Bcl-2 protein family and rasagiline. The results are discussed in concern to intracellular mechanism underlying anti-apoptotic function of rasagiline analogues.
Maruyama
W
W
Laboratory of Biochemistry and Metabolism, Department of Basic Gerontology, National Institute for Longevity Sciences, Obu, Aichi, Japan.
Akao
Y
Y
Youdim
M B
MB
Davis
B A
BA
Naoi
M
M
D021581:Active Transport, Cell Nucleus / Q000502:physiology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D002460:Cell Line; D002467:Cell Nucleus / Q000201:enzymology*; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000378:metabolism*; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D007189:Indans / Q000494:pharmacology* / Q000627:therapeutic use; D008564:Membrane Potentials / Q000187:drug effects; D008928:Mitochondria / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology; D009498:Neurotoxins / Q000737:chemistry / Q000494:pharmacology; D010300:Parkinson Disease / Q000188:drug therapy; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D012490:Salsoline Alkaloids / Q000737:chemistry / Q000494:pharmacology*; D015398:Signal Transduction; D044005:Tetrahydroisoquinolines; D014162:Transfection
D007189:Indans; D018696:Neuroprotective Agents; D009498:Neurotoxins; D019253:Proto-Oncogene Proteins c-bcl-2; D012490:Salsoline Alkaloids; D044005:Tetrahydroisoquinolines; C031967:rasagiline; C032837:salsoline; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases