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Neuroprotection by pharmacologic blockade of the GAPDH death cascade.

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.

Pubmed ID: 16505364

Authors

  • Hara MR
  • Thomas B
  • Cascio MB
  • Bae BI
  • Hester LD
  • Dawson VL
  • Dawson TM
  • Sawa A
  • Snyder SH

Journal

Proceedings of the National Academy of Sciences of the United States of America

Publication Data

March 7, 2006

Associated Grants

  • Agency: NIDA NIH HHS, Id: DA-00074
  • Agency: NIDA NIH HHS, Id: DA-00266
  • Agency: NIMH NIH HHS, Id: MH-069853
  • Agency: NINDS NIH HHS, Id: NS-38377

Mesh Terms

  • Animals
  • Antiparkinson Agents
  • Apoptosis
  • Cell Line
  • Glyceraldehyde-3-Phosphate Dehydrogenases
  • Humans
  • In Vitro Techniques
  • MPTP Poisoning
  • Male
  • Mice
  • Nerve Degeneration
  • Neuroprotective Agents
  • Nitric Oxide
  • Nuclear Proteins
  • Oxepins
  • Parkinson Disease
  • Selegiline
  • Ubiquitin-Protein Ligases