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Vol. 57, Issue 1, 2-12, January 2000
Departments of Neurology (G.W.C., R.M.E.C.-R., N.A.T., A.P.,
K.L.B.B., W.G.T.) and Physiology and Biophysics (K.L.B.B.), Mount Sinai
School of Medicine, New York, New York
Antisense oligonucleotides against the glycolytic enzyme
glyceraldehyde-3-phosphate dehydrogenase (GAPDH) are able to reduce some forms of apoptosis. In those forms, overall GAPDH levels increase
and the enzyme accumulates in the nucleus. The monoamine oxidase B
(MAO-B) inhibitor, (
)-deprenyl (DEP), its metabolite ()-desmethyldeprenyl, and a tricyclic DEP analog, CGP3466, can reduce
apoptosis independently of MAO-B inhibition and have been found to bind
to GAPDH. We used neuronally differentiated PC12 cells to show that
DEP, DES, and CGP3466 reduce apoptosis caused by serum and nerve growth
factor withdrawal over the concentration range of 10
to
1013 M. We provide evidence that the DEP-like compounds
bind to GAPDH in the PC12 cells and that they prevent both the
apoptotic increases in GAPDH levels and nuclear accumulation of GAPDH.
In vitro, the compounds enhanced the conversion of NAD+ to
NADH by GAPDH in the presence of AUUUA-rich RNA and converted GAPDH
from its usual tetrameric form to a dimeric form. Using cell lysates,
we found a marked increase in rates of NAD+ to NADH
conversion in early apoptosis, which was returned toward control values
by the DEP-like compounds. Accordingly, the DEP-like compounds appear
to decrease glycolysis by preventing the GAPDH increases in early
apoptosis. GAPDH dimer may not have the capacity to contribute to
apoptosis in a similar manner to the tetramer, which might account for
the antiapoptotic capacity of the compounds. These actions on GAPDH,
rather than MAO-B inhibition, may contribute to the improvements in
Parkinson's and Huntington's diseases found with DEP treatment.
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