As the average life span increases, the prevalence of many neurodegenerative diseases is also increasing. Characteristics of these disorders is the demise of selected neuronal populations. A prototypical example is idiopathic Parkinson's Disease (PD) where dopaminergic neurons are preferentially affected. Heavily favored theories of neurodegeneration in PD involve mechanisms of oxidative stress. Evidence of these processes exists in PD, yet how this general mechanism leads to selective vulnerability is unknown. The serendipitous discovery of the selective neurotoxin 1-methyl-4phenyl- 1,2,3,6-tetrahydropyridine (MPTP) has provided an excellent model of selective neuronal demise which greatly parallels that seen in PD. Recent investigations reveal that nitric oxide (NO) plays an integral role in MPTP-induced neurotoxicity in rodents and primates. Pharmacologic inhibitors of nitric oxide synthase (NOS) or genetic deletions of neuronal NOS protect against MPTP-induced neurotoxicity. However, the relative contribution of NO and other reactive oxygen species (ROS) as well as the identity of their downstream targets remain unknown. We propose to investigate the sources and roles of NO and ROS in MPTP- induced parkinsonism and identify the primary downstream targets which mediate neuronal death. One potential activator of downstream targets is peroxynitrite, a potent ROS formed from the reaction of NO with superoxide anion. Peroxynitrite can cause nitration and damage DNA. The enzyme poly(ADP-ribose) polymerase(PARP) is activated by damage DNA resulting in rapid depletion of energy essential for survival. Inhibitors of PARP and genetic knockouts of PARP provide substantial neuroprotection from ischemic damage, NMDA and NO-induced neurotoxicity. These studies place PARP in a pivotal role for executing neuronal cell death. The effects of NO and ROS, independently and in combination, upon PARP will be examined in vivo using both pharmacologic methods and transgenic mice (including PARP knockouts). The clarification of cellular death pathways mediated by the MPTP neurotoxin should provide insight into neurodegenerative disorders including PD.
| Mandir, A S; Poitras, M F; Berliner, A R et al. (2000) NMDA but not non-NMDA excitotoxicity is mediated by Poly(ADP-ribose) polymerase. J Neurosci 20:8005-11 |
| Mandir, A S; Przedborski, S; Jackson-Lewis, V et al. (1999) Poly(ADP-ribose) polymerase activation mediates 1-methyl-4-phenyl-1, 2,3,6-tetrahydropyridine (MPTP)-induced parkinsonism. Proc Natl Acad Sci U S A 96:5774-9 |
