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Tuesday, October 31, 2017
Nitric Oxide Signaling in Neurodegeneration and Cell Death
In
this tribute to Solomon H. Snyder (Sol) we discuss the mechanisms by
which nitric oxide (NO) kills neurons. We provide a historical
perspective regarding the discovery that glutamate excitotoxicity is
mediated by NO. It also contains a discussion of the discovery that
neuronal nitric oxide synthase (nNOS) catalytic activity accounts for
NADPH diaphorase activity and its localization in the central nervous
system. NADPH diaphorase/nNOS neurons are unique in that they are
resistant to toxic effects of excess glutamate and that they are
resistant to neurodegeneration in a variety of neurodegenerative
diseases. NADPH diaphorase/nNOS neurons are resistant to neurotoxicity
and neurodegeneration through the overexpression of manganese superoxide
dismutase. The review also delves into the mechanisms by which NO kills
neurons including NO's activation of the glyceraldehyde-3-phosphate
dehydrogenase-dependent cell pathway. In addition, there is a review of
parthanatos in which NO combines with the superoxide anion (
) to form peroxynitrite (ONOO−)
that damages DNA and activates poly (ADP-ribose) (PAR) polymerase
(PARP). This ultimately leads to activation of the PARP-dependent
apoptosis-inducing factor-associated nuclease, the final executioner in
NO-dependent cell death. Finally, there is a discussion of potential
targets that are under development that target the mechanisms by which
NO kills neurons.
Keywords
NADPH diaphorase
Nitric oxide
Neuronal nitric oxide synthase
Parthanatos
Poly (ADP-ribose) polymerase
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