Cellular and Molecular Neurobiology

, Volume 26, Issue 4–6, pp 525–536 | Cite as

Nitric Oxide–GAPDH–Siah: A Novel Cell Death Cascade

  • Makoto R. Hara
  • Solomon H. SnyderEmail author


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.


GAPDH nitric oxide nitric oxide synthase S-nitrosylation siah apoptosis parkinson's disease huntington's disease 



This work was supported by USPHS grants DA-00266 and Research Scientist AwardDA00074 (SHS). We thank Dr. Akira Sawa, Dr. Byoung-Il Bae, and Matthew B. Cascio for their helpful comments. We thank Dr. Peter Waldmeier for providing us TCH346.


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Copyright information

© Springer Science+Business Media, Inc. 2006

Authors and Affiliations

  1. 1.The Solomon H. Snyder Department of NeuroscienceJohns Hopkins University School of MedicineBaltimoreUSA
  2. 2.Department of Psychiatry and Behavioral SciencesJohns Hopkins University School of MedicineBaltimoreUSA

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