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Vol. 53, Issue 4, 701-707, April 1998
Group on Cellular Neurobiology, Josai University, Sakado, Saitama
350-02, Japan (R.I., K.S.),
Ono Pharmaceutical Company, Ltd., Chuo-ku,
Osaka 541, Japan (M.T., N.K.), and
Section on Molecular Neurobiology,
Biological Psychiatry Branch, National Institute of Mental Health,
National Institutes of Health, Bethesda, Maryland 20892 (D.-M.C.)
We recently reported that overexpression of glyceraldehyde-3-phosphate
dehydrogenase (GAPDH; EC 1.2.1.12) is directly involved in cytosine
arabinonucleoside (ara-C)- and low K+-induced neuronal
death of cultured cerebellar granule cells. The former is entirely due
to apoptosis, whereas the latter involves both apoptosis and necrosis.
We examined the subcellular distribution of the overexpressed GAPDH
occurring during apoptosis by using both subcellular fractionation and
immunocytochemistry with a monoclonal antibody directed against this
overexpressed protein. When immature cerebellar neurons were exposed to
ara-C, an overexpression of GAPDH was observed, primarily in the
nuclear fraction. In contrast, low K+ exposure of mature
cerebellar neurons induced the overexpression of GAPDH not only in the
nuclear fraction but also in the mitochondrial fraction. In both
paradigms, no significant change of GAPDH levels occurred in the
microsomal and cytosolic fractions. Moreover, pretreatment with GAPDH
antisense oligonucleotide or classic apoptotic inhibitors clearly
suppressed the accumulation of GAPDH protein in these subcellular loci.
This discrete nuclear localization of GAPDH during apoptosis was
supported further by immunoelectron microscopy. Quantitative assessment
of GAPDH immunogold labeling revealed that a ~5-fold increase in the
intensity of gold particles was observed within the nucleus of
apoptotic cells. Thus, the current results raise the possibility that
neuronal apoptosis may be triggered by GAPDH accumulation in the
nucleus, resulting in perturbation of nuclear function and ultimate
cell death.
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