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.
Hara
Makoto R
MR
Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Thomas
Bobby
B
Cascio
Matthew B
MB
Bae
Byoung-Il
BI
Hester
Lynda D
LD
Dawson
Valina L
VL
Dawson
Ted M
TM
Sawa
Akira
A
Snyder
Solomon H
SH
D000818:Animals; D000978:Antiparkinson Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D002460:Cell Line; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000037:antagonists & inhibitors* / Q000502:physiology; D006801:Humans; D066298:In Vitro Techniques; D020267:MPTP Poisoning / Q000473:pathology / Q000503:physiopathology; D008297:Male; D051379:Mice; D009410:Nerve Degeneration / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009569:Nitric Oxide / Q000378:metabolism; D009687:Nuclear Proteins / Q000502:physiology; D010082:Oxepins / Q000494:pharmacology; D010300:Parkinson Disease / Q000188:drug therapy; D012642:Selegiline / Q000494:pharmacology; D044767:Ubiquitin-Protein Ligases / Q000502:physiology; D000098563:Seven in Absentia Proteins
D000978:Antiparkinson Agents; D018696:Neuroprotective Agents; D009687:Nuclear Proteins; D010082:Oxepins; C111178:dibenzo(b,f)oxepin-10-ylmethyl-methyl-prop-2-ynyl-amine; D012642:Selegiline; D009569:Nitric Oxide; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases; D044767:Ubiquitin-Protein Ligases; D000098563:Seven in Absentia Proteins