Neuroprotection by pharmacologic blockade of the GAPDH death cascade

Makoto R. Hara, Bobby Thomas, Matthew B. Cascio, Byoung Il Bae, Lynda D. Hester, Valina L. Dawson, Ted M. Dawson, Akira Sawa, Solomon H. Snyder

Research output: Contribution to journalArticle

186 Scopus citations

Abstract

Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) participates in a cell death cascade wherein a variety of stimuli activate nitric oxide (NO) synthases with NO nitrosylating GAPDH, conferring on it the ability to bind to Siah, an E3-ubiquitin-ligase, whose nuclear localization signal enables the GAPDH/Siah protein complex to translocate to the nucleus where degradation of Siah targets elicits cell death. R-(-)-Deprenyl (deprenyl) ameliorates the progression of disability in early Parkinson's disease and also has neuroprotective actions. We show that deprenyl and a related agent, TCH346, in subnanomolar concentrations, prevent S-nitrosylation of GAPDH, the binding of GAPDH to Siah, and nuclear translocation of GAPDH. In mice treated with the dopamine neuronal toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), low doses of deprenyl prevent binding of GAPDH and Siah1 in the dopamine-enriched corpus striatum.

Original languageEnglish (US)
Pages (from-to)3887-3889
Number of pages3
JournalProceedings of the National Academy of Sciences of the United States of America
Volume103
Issue number10
DOIs
StatePublished - Mar 7 2006

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Keywords

  • Apoptosis
  • Nitric oxide
  • Parkinson's disease
  • S-nitrosylation
  • Siah

ASJC Scopus subject areas

  • General

Cite this

Hara, M. R., Thomas, B., Cascio, M. B., Bae, B. I., Hester, L. D., Dawson, V. L., Dawson, T. M., Sawa, A., & Snyder, S. H. (2006). Neuroprotection by pharmacologic blockade of the GAPDH death cascade. Proceedings of the National Academy of Sciences of the United States of America, 103(10), 3887-3889. https://doi.org/10.1073/pnas.0511321103