Apoptosis inducing factor and PARP-mediated injury in the MPTP mouse model of Parkinson's disease.
Experimental intoxication models are used to study the more common sporadic form of Parkinson's disease (PD). 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyrimidine (MPTP) animal models of PD provide a valuable and predictive tool to probe the molecular mechanisms of dopamine neuronal cell death in PD. MPTP is a powerful neurotoxin that induces neuronal degeneration in the substantia nigra pars compacta and produces PD-like symptoms in several mammalian species tested, a feat not yet accomplished in genetically engineered mice expressing human genetic mutations. The mechanisms of MPTP-induced neurotoxicity are not yet fully understood but involve activation of N-methyl-D-aspartate (NMDA) receptors by glutamate, production of NO by nNOS and iNOS, oxidative injury to DNA, and activation of the DNA damage-sensing enzyme poly (ADP-ribose) polymerase (PARP). Recent experiments indicate that translocation of a mitochondrial protein apoptosis inducing factor (AIF) from mitochondria to the nucleus depends on PARP activation and plays an important role in excitotoxicity-induced cell death. This article briefly reviews the experimental findings regarding excitotoxicity, PARP activation, and AIF translocation in MPTP toxicity and dopaminergic neuronal cell death.
Wang
Hongmin
H
Department of Neurology, Neuroscience, and Physiology, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.
Shimoji
Mika
M
Yu
Seong-Woon
SW
Dawson
Ted M
TM
Dawson
Valina L
VL
D000818:Animals; D051033:Apoptosis Inducing Factor; D016923:Cell Death / Q000502:physiology; D004249:DNA Damage; D004195:Disease Models, Animal; D005420:Flavoproteins / Q000378:metabolism*; D000882:Haplorhini; D006801:Humans; D020267:MPTP Poisoning / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology; D008565:Membrane Proteins / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism*; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D011506:Proteins / Q000235:genetics / Q000378:metabolism*
C494829:AIFM1 protein, human; D051033:Apoptosis Inducing Factor; D005420:Flavoproteins; D008565:Membrane Proteins; D011506:Proteins; D009569:Nitric Oxide; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases