Role of Manganese in Neurodegenrative Disease

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DESCRIPTION (provided by applicant): Recent studies have shown that chronic exposures to manganese (Mn) are associated with an increased risk for the development of neurodegenerative diseases, such as Parkinsonism. Concern over the potential neurotoxicity of low but chronic Mn exposure has increased in light of the incorporation of MMT into gasoline. The effects of Mn exposure in in vivo rodent models has focused on Mn-induced depletion of striatal dopamine, whereas non-human primate studies have more commonly shown gliosis in the globus pallidus. Also, most studies have utilized relatively high Mn exposures, while only a few have investigated the effects of chronic low-level Mn exposures. Here we are proposing that the locus of Mn toxicity may depend on the total cumulative Mn dose, such that more sensitive GABAergic systems of the globus pallidus are targeted at lower relative doses, while dopaminergic systems of the nigro-striatal pathway become involved at higher doses. To validate this, there is a need to investigate the effects of Mn on specific brain nuclei and neurotransmitter systems as a function of Mn exposure regimens in order to better characterize the overall susceptibility of the basal ganglia to Mn effects. Moreover, there is justified concern that increased chronic low-level Mn exposure may further undermine the functionality of the basal ganglia in susceptible populations in the early stages of neurodegenerative disease, and accelerate the emergence of neuromotor dysfunction. The specific aims of this study are to: (1) Determine the progression of Mn effects on brain regional Mn distribution, and neurochemical and neuromotor function, across different durations and low level doses of Mn exposures in a whole animal rodent model. And (2) Determine the effect(s) and underlying interaction(s) of Mn exposure on neurotoxicity and neuromotor performance in a rodent model of asymptomatic Parkinsonism, as a model of a susceptible population. These Aims will be pursued through several sub-aims focusing on the following major outcomes: (i) A Functional Observational Battery (FOB) of neuromotor performance; (ii) Particle induced X-ray emission (PIXE) analyses of in situ brain regional Mn levels; (iii) Neurochemical measures of GABAergic and dopaminergic metabolism/status in specific brain regions, and; (iv) Investigation of specific mechanisms underlying the Mn - GABAergic effect using cell culture models. These proposed studies will significantly extend our knowledge of chronic low level Mn neurotoxicity, by pursuing a unifying hypothesis of action of low-level chronic Mn exposure, and by investigating neurochemical and neuromotor outcomes of Mn exposure in conjunction with a moderate degree of sub-threshold Parkinsonism.