GI Endotoxin as an Environmental Trigger in an alpha-Synuclein Transgenic Mouse

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DESCRIPTION (provided by applicant): Parkinson Disease (PD) is a common neurodegenerative disease affecting ~1 million people in the United States. While loss of substantia nigra dopaminergic neurons is primarily responsible for the characteristic parkinsonian movement disorder, non-motor disabilities including dementia, depression, gastrointestinal dysfunction, and autonomic instability arise from neurodegeneration elsewhere in the central, enteric and autonomic nervous systems. The cause of most PD is unknown despite decades of research. Family studies, twin studies, and genetic association studies in Parkinson disease (PD) support the view that PD is a complex systemic nervous system disorder caused by one or more environmental agents acting on genetically vulnerable individuals. The genetic predisposition can be strong, as in the rare, familial forms of PD caused by missense or copy number mutations in the 1-synuclein gene (SNCA), or subtle, as in the more common sporadic disease, where genetic association studies indicate that polymorphic variants at the SNCA locus contribute to genetic predisposition. Epidemiological and experimental observations have suggested many different environmental agents may contribute to the development of PD. These include viral infection, heavy metals, bacterial toxins, microbe-induced inflammation, and chemical agents including pesticides. The balance between genetic predisposition and environmental insult is likely to be different depending on the strength of the predisposition. The intensity of environmental exposure required to cause disease is likely inversely related to the degree of genetic vulnerability: the greater the genetic susceptibility, the less the environmental exposure required and the more apparently heritable the disease will appear to be. Exposure to the environmental agents implicated in PD is probably via the gastrointestinal (GI) tract (although inhalation exposing the olfactory nerves is also possible), suggesting that the enteric nervous system (ENS), which would be on the front lines of exposure to these environmental agents, might be affected early in the disease. Indeed, GI dysfunction is well documented to occur years to decades before the motor signs in PD patients. Braak and his colleagues reported that the youngest individuals in their large autopsy series showed pathological changes of PD only in the enteric nervous system (ENS), while PD pathology in the CNS appeared at older ages, affecting predominantly the brain stem, as well as in the ENS. Ultimately, CNS pathology in the midbrain (including substantia nigra) and cortex was seen in still older individuals. We propose to test the hypothesis that exposure of genetically predisposed mice to pathogenic environmental exposures through the GI tract will model PD and that early ENS dysfunction not only temporally precedes CNS dysfunction but actually contributes causally to it by increasing the exposure to these agents. We have developed a series of transgenic mice engineered to mimic genetically vulnerable individuals with familial PD due to SNCA mutations. These mice overexpress either wildtype or mutant (A53T and A30P) human 1-synuclein from a P1 artificial chromosome containing the human SNCA locus. Mice expressing either of the two mutant, but not wildtype, 1-synucleins have ENS dysfunction as early as 3 months of age, with prolonged Gl transit time and decreased colonic motility, but minimal CNS dysfunction and CNS neuronal loss. We will expose these transgenic animals to gram-negative endotoxin and rotenone, two agents frequently considered as environmental toxins most strongly implicated in PD. We will ask whether the enteric nervous system defect in our 1Syn transgenic models will (1) cause changes in distribution and composition of gut flora and exposure to intestinal bacteria, (2) enhance the absorption of endotoxin leading to systemic inflammatory effects and neurological defects, and (3) increase absorption and neurotoxicity of rotenone, a pesticide previously shown in cellular and animal models to cause neurodegeneration. PUBLIC HEALTH RELEVANCE: Evidence is accumulating that environmental exposures in individuals genetically predisposed to Parkinson disease are critical in the development of the disease. The applicant wants to know if mice, engineered to mimic the genetic make-up of humans with a form of hereditary Parkinson disease, are at significantly increased risk for developing a mouse equivalent of Parkinson disease when exposed through their gastrointestinal tract to two different environmental agents thought to have a role in causing human PD: endotoxin made by normal bacteria in the gut and the commonly used pesticide rotenone. The ultimate goal is to study in detail the role of gastrointestinal exposure to environmental agents in the development of neurodegeneration in a model of the natural human disease. By understanding the disease process, we can identify points at which interventions could slow or stop its progression.