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Neuroprotection by pharmacologic blockade of the GAPDH death cascade.

http://www.ncbi.nlm.nih.gov/pubmed/16505364

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 RIS Download

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