(from abstract): This proposal is submitted to pursue our exploration of the pathogenesis of Parkinson's disease (PD). Pertinent to this goal, we have found that synuclein expression is increased in the mouse midbrain after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration, a toxin that damages the substantia nigra pars compacta (SNpc) as seen in Parkinson's disease. Mutations in the alpha synuclein gene are associated with the development of a familial form of PD> However, to date, the link between synuclein and SNpc neurodegeneration is unknown. To acquire a better understanding about this relationship, Specific Aim I will assess the time course of synuclein mRNA and protein expression alterations in selected brain regions following MPTP regimens that induce SNpc neuronal apoptotic or necrotic death. To determine whether increased expression of synuclein is specific to MPTP-induced neuronal death, Specific Aim II will explore the topographical and temporal expression of synuclein in another model of SNpc degeneration such as that produced by the mutant copper/zinc superoxide dismutase (SOD1) G93A enzyme. Changes in synuclein's secondary structure due to mutation or tyrosine nitration may underlie its toxicity. To assess this possibility, Specific Aim III will determine: (I) the magnitude and location of tyrosine nitration of synuclein following exposure of PC-12 cells to peroxynitrite and to MPTP's active metabolite, 1-methyl-4-phenylpyridinium (MPP+); (ii) the time course of synuclein tyrosine nitration in MPTP-treated mice; and (iii) the requirement for superoxide and nitric oxide (NO) in synuclein nitration by administering Altered pre-synaptic protein synuclein may impair synaptic machinery including MPTP metabolism. Thus, to elucidate whether modulation of synuclein expression can affect susceptibility to MPTP, Specific Aim IV will correlate the severity of MPP+-induced toxicity with the level of synuclein expression in PC-12 cell in which contains a comprehensive set of experiments which should shed light on the role of synuclein in experimental models of SNpc degeneration and possibly in Parkinson's disease.
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