Parkinson's disease (PD) is a neurodegenerative disorder associated with dopamine (DA) cell loss in the substantia nigra (SN). Recent evidence supports the involvement of a toxin in the cause of PD. Moreover, impairments in detoxifying mechanisms identified in PD patients suggest that predisposition to the disease may be related to the inability to detoxify the putative causal agent. The applicant is a clinically trained neurologist with a special interest in PD. The focus of this proposal is the study of possible causal and predisposing mechanisms for PD and has been designed to explore two observations made by the applicant. First, transgenic mice with increased superoxide dismutase (SOD) activity are resistant to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a toxin which damages SN DA cells as seen in PD. Further studies are needed to investigate the role of SOD, a key enzyme in cellular defenses against superoxide radicals, in the MPTP model and in PD. Second, there is an inverse relationship between the number of SN-DA cells an MPTP sensitivity in two different mouse strains. Further investigations are required to explore the basis of this relationship.
Specific Aim (SA) I will examine in selected brain regions whether strain- and age-dependent MPTP sensitivity in mice are related to differences in activity of SOD and/or in number of neurons expressing SOD protein and mRNA. To further understand the mechanisms involved in the resistance of SOD-transgenic mice to mPTP, SA II will examine the effects of 1-methyl-4-phenylpyridinium (MPP+), the toxic metabolite of mPTP, and of other specific toxins on cultured DA cells from SOD-transgenic and nontransgenic mice. In SA III, activity of SOD and number of neurons expressing SOD protein and mRNA will be examined in post-mortem PD brains. Also examined will be SOD activity in blood samples from PD patients. Mutations for one SOD isoenzyme have recently been associated with familial amyotrophic lateral sclerosis (ALS), which suggests that, like PD, ALS may be caused by free radicals. Thus, post-mortem and blood sample studies for SOD will also be performed in ALS. In SA IV, the relationship between the number of SN DA neurons and MPTP sensitivity will be examined in different mouse strains in which the number of nigral neurons will be experimentally diminished by a neonatal striatal quinolinic acid lesion. SA V will examine the developmental basis for differences in nigral neuron number among different mouse strains as they relate to number of precursor cells or to degree of developmental cell death. The studies outlined in this proposal will provide further insight into the possible role of free radicals in the pathogenesis of PD and the role played by determinants of nigral neuron number.
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