PhIP-induced neurodegeneration: mechanisms and relevance to Parkinson's disease

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DESCRIPTION (provided by applicant): The causes of most Parkinson's disease (PD) cases are unknown (~90% are "sporadic"), while ~10 % are due to purely inherited factors. Environmental factors have long been suspected, but no toxicant has been convincingly identified. Numerous diverse classes of compounds, including pesticides and solvents have been linked to PD. This proposal tests the hypothesis that: exposure to the heterocyclic amine, 2-amino-1-methyl-6- phenylimidazo[4,5-b]pyridine (PhIP), a known carcinogen in rodents, replicates key features of human Parkinson's disease (PD). Currently, there are little preliminary data on the neurological effects of chronic PhIP. However, four key factors have led to proposing a role for PhIP in PD-relevant neurodegeneration. 1) A preliminary study from members of our group showing PD-relevant motor deficits in mice 2) Published dopaminergic effects of structurally related heterocylic amines in rats 3) Potential for high-level human consumption. PhIP is the most abundant amino-imidazoazaarene isolated from the crust of cooked meat (up to 15ug/kg uncooked meat) and 4) PhIP and PhIP metabolites cross the blood-brain barrier and, therefore, may have direct effects on distinct neuronal nuclei. The major goals of this proposal are to: 1) Determine if chronic administration of PhIP in the rat reproduces the key features of PD and 2) Identify potential mechanisms of toxicity using in vitro approaches. In this proposal, the following aims will be carried out: Aim 1. To determine if chronic PhIP administration replicates the key features of PD. Aim 2. To identify mechanisms of neurotoxicity of PhIP using a primary midbrain culture system. Success of this proposal would lead to at least three major advances in PD research. 1. Identification of a possible causative factor. PhIP is a common toxicant produced in meat preparation and may be consumed in single high doses and chronically vs. most rarely encountered dopaminergic toxicants. Success of this proposal would likely prompt epidemiological studies. Further, alterations in meat preparation are available, reducing PhIP formation and a potential PD-relevant exposure. 2. Development of a new PD model. There are numerous PD models, each with advantages/ disadvantages. None have adequately considered dietary factors. Current models have also failed to predict clinical trial successes and a novel model may prove to be more successful. 3. New PD mechanisms. If PhIP exposure reproduces the key PD features, mechanistic studies would be expected to identify novel pathogenic pathways that may be therapeutic targets. In summary, using both in vivo and in vitro systems we will carefully characterize neurodegeneration after PhIP exposure and preliminarily identify mechanisms of toxicity relevant to effects on the nigrostriatal dopamine system.