A Murine Model of Genetic and Environmental Neurotoxicant Action
Annual rept. 1 Sep 2001-31 Aug 2002
ROCHESTER UNIV NY
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This project studies interactions between genes, the environment, and age in causing mouse Parkinsonism. We use mice overexpressing wild-type or a doubly mutated form of human a-synuclein ha-SYN. We created and characterized these two constructs on a DNA, RNA, and protein levels. Both the wild-type and doubly mutated lines express functional ha-SYN in dopaminergic terminals. The doubly-mutated ha-SYN line declines in locomotor behavior, levels of dopamine DA and metabolites, and number of TH neurons in the substantia nigra pars compacta throughout its life-span. These changes resemble those seen in human Parkinsonism. This line also fails to respond to a presynaptic dose of apomorphine, but is supersensitive to a higher postsynaptic dose of apomorphine consistent with denervation supersensitivity. We demonstrate age and gender specific effects of combined neurotoxicants. We report a plausible mechanism for the potentiation of both MPTP and paraquat toxicity by selective dithiocarbamates.
- Medicine and Medical Research