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1: Proc Natl Acad Sci U S A. 2006 Mar 7;103(10):3887-9. Epub 2006 Feb 27.
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Neuroprotection by pharmacologic blockade of the GAPDH death cascade.

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

Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.

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.

Publication Types:
PMID: 16505364 [PubMed - indexed for MEDLINE]

PMCID: PMC1450161