Genetic Susceptibility Loci in Mouse Neurotoxic Parkins*

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DESCRIPTION (provided by applicant) The cause(s) of idiopathic Parkinson's disease (PD) in man remains unknown, but reflects an individual's combined risks associated with genetic background, life-long environmental exposures and age. The role of genotype in contributing to PD varies depending on the presence of a genetic mutation or a polymorphism that contributes to the alteration of a gene product or function. The role of the environment in idiopathic PD also varies from strong for certain neurotoxicants such as MPTP to weaker for pesticides and heavy metals. The interaction between genetic and environmental risk factors in man and mouse is poorly understood. Mouse models of PD based on genetic manipulations, neurotoxicant exposure or combined genetic and neurotoxicant exposures are useful for exploring mechanisms of neuronal loss and dysfunction. Recent breakthroughs in several areas of genetics and biotechnology will help define the roles of genes and neurotoxicants in PD. We will map Quantitative Trait Loci (QTL) in mice that play a role in mouse models of PD. We will measure baseline locomotor activity, striatal dopamine and metabolite levels, and total substantia nigra pars compacta (SNpc) neuron number in 15 inbred strains of mice treated with saline or with MPTP, paraquat, or paraquat plus maneb. We will use the association mapping procedure and mouse single nucleotide polymorphism (SNP) database created by Peltz and colleagues to map QTL for these traits in the absence or presence of a neurotoxicant. We will use permutation tests to generate appropriate experiment-wise thresholds for declaring a QTL significant. We propose a novel and innovative method for mapping QTL contributing to the adverse effects of environmental neurotoxicants resulting in the PDP in mice. Mapping of QTL will ultimately lead to a variety of studies in mice resulting in the identification of the specific genes involved and their mechanism of action in contributing to PD. Our ultimate goal is to identify specific genes, their polymorphisms, and how they interact with the environment in predisposing man to PD.