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A Murine Model of Genetic and Environmental Neurotoxicant Action

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Annual rept. 1 Sep 2000-31 Aug 2001

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This project studies interactions between genes, environment, and age in causing mouse Parkinsonism. We use mice overexpressing wild-type or a doubly mutated form of human alpha-synuclein halpha-SYN. We created and characterized these two constructs on DNA, RNA, and protein levels. Both the wild-type and doubly mutated lines express functional human alpha-SYN in dopaminergic terminals as demonstrated by altered locomotor responses to systemic amphetamine and overexpression of the dopamine transporter. Both constructs are more sensitive to acute doses of MPTP. The doubly-mutated ha-SYN line has altered levels of motor behavior and altered levels of dopamine DA and metabolites throughout its age span. At a young age, this line is hyperactive, progressing to normal levels of activity in middle age, but becoming hypoactive at an old age. These changes are paralleled by alterations in DA and metabolites and resemble those seen in human Parkinsonism. Finally, the doubly-mutated halpha-SYN line is very sensitive to the combination of systemic neurotoxicants, maneb and paraquat demonstrating significant reductions in locomotor activity, DA, and substantia nigra neuron number. We intend to continue our aging and neurotoxicant studies in the next year and establish our somatic mosaic lines to study the role of selective aggregation as a mechanism of toxicity.

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  • Biochemistry
  • Medicine and Medical Research

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