Neuroprotection by pharmacologic blockade of the GAPDH death cascade.

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.

• Authors: 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
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 103 Issue 10 Pg. 3887-9 (Mar 07 2006) ISSN: 0027-8424 [Print] United States
• PMID: 16505364 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antiparkinson Agents
• Neuroprotective Agents
• Nuclear Proteins
• Oxepins
• dibenzo(b,f)oxepin-10-ylmethyl-methyl-prop-2-ynyl-amine
• Selegiline
• Nitric Oxide
• Glyceraldehyde-3-Phosphate Dehydrogenases
• Ubiquitin-Protein Ligases
• seven in absentia proteins

Topics

• Animals
• Antiparkinson Agents (pharmacology)
• Apoptosis (drug effects, physiology)
• Cell Line
• Glyceraldehyde-3-Phosphate Dehydrogenases (antagonists & inhibitors, physiology)
• Humans
• In Vitro Techniques
• MPTP Poisoning (pathology, physiopathology)
• Male
• Mice
• Nerve Degeneration (pathology, physiopathology, prevention & control)
• Neuroprotective Agents (pharmacology)
• Nitric Oxide (metabolism)
• Nuclear Proteins (physiology)
• Oxepins (pharmacology)
• Parkinson Disease (drug therapy)
• Selegiline (pharmacology)
• Ubiquitin-Protein Ligases (physiology)