Nitric oxide-GAPDH-Siah: a novel cell death cascade.

Makoto R. Hara, Solomon H Snyder

Research output: Contribution to journalArticle

Abstract

1. Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is an extremely abundant glycolytic enzyme, and exemplifies the class of proteins with multiple, seemingly unrelated functions. Recent studies indicate that it is a major intracellular messenger mediating apoptotic cell death. This paper reviews the GAPDH cell death cascade and discusses its clinical relevance. 2. A wide range of apoptotic stimuli activate NO formation, which S-nitrosylates GAPDH. The S-nitrosylation abolishes catalytic activity and confers upon GAPDH the ability to bind to Siah, an E3-ubiquitin-ligase, which translocates GAPDH to the nucleus. In the nucleus, GAPDH stabilizes the rapidly turning over Siah, enabling it to degrade selected target proteins and affect apoptosis. 3. The cytotoxicity of mutant Huntingtin (mHtt) requires nuclear translocation which appears to be mediated via a ternary complex of GAPDH-Siah-mHtt. The neuroprotective actions of the monoamine oxidase inhibitor R-(-)-deprenyl (deprenyl) reflect blockade of GAPDH-Siah binding. Thus, novel cytoprotective therapies may emerge from agents that prevent GAPDH-Siah binding.

Original languageEnglish (US)
Pages (from-to)527-538
Number of pages12
JournalCellular and Molecular Neurobiology
Volume26
Issue number4-6
StatePublished - Jul 2006

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Glyceraldehyde-3-Phosphate Dehydrogenases
Cell death
Nitric Oxide
Cell Death
Selegiline
Monoamine Oxidase Inhibitors
Ubiquitin-Protein Ligases
Cytotoxicity
Catalyst activity
Proteins
Apoptosis

ASJC Scopus subject areas

  • Neuroscience(all)
  • Clinical Biochemistry
  • Cell Biology
  • Genetics

Cite this

Nitric oxide-GAPDH-Siah : a novel cell death cascade. / Hara, Makoto R.; Snyder, Solomon H.

In: Cellular and Molecular Neurobiology, Vol. 26, No. 4-6, 07.2006, p. 527-538.

Research output: Contribution to journalArticle

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