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.
Mesh Terms:
Animals, Antiparkinson Agents, Apoptosis, Cell Line, Glyceraldehyde-3-Phosphate Dehydrogenases, Humans, MPTP Poisoning, Male, Mice, Nerve Degeneration, Neuroprotective Agents, Nitric Oxide, Nuclear Proteins, Oxepins, Parkinson Disease, Selegiline, Ubiquitin-Protein Ligases
Proc. Natl. Acad. Sci. U.S.A.
Date: Mar. 07, 2006
Download Curated Data For This Publication
140625
Switch View:
  • Interactions 2