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The Parkinson's InstituteEnvironmental, Genetic, & Cellular Determinants of Parkinson's Disease Project DescriptionAn overwhelming number of epidemiological studies show an inverse correlation between smoking and Parkinson’s disease; stated another way, cigarette smoking appears to reduce the risk of Parkinson’s disease. Thus, in contrast to the negative effects generally associated with tobacco products, there appears to be a component in tobacco products that may actually protect against Parkinson’s disease. We believe that these observations point to a novel and important research opportunity, and have made a commitment to intensively investigate this phenomenon in the laboratory with the goal of finding scientific leads that could lead to new strategies to protect against this neurological disorder. This would be most welcome as the drugs currently available for the treatment of Parkinson’s disease are mainly symptomatic and are typically short acting in nature (hours). However, this task is likely to be daunting, as there are about 4000 chemicals in cigarette smoke. This will make identification of the putative “neuroprotective” component in cigarette smoke a difficult task. Because recent studies suggest that nicotine may be the active neuroprotective component in cigarette smoke, we are doing experiments with different experimental model systems to study how nicotine may reduce the occurrence of Parkinson’s disease. Project 1: Genes, Environment and Parkinson's Disease : Studies in 4 Unique Cohorts Principal Investigator: Caroline M. Tanner, M.D., Ph.D. The cause of Parkinson's disease (PD) is not known. Although several genetic forms of parkinsonism have been identified, these are rare, and most Parkinson's disease is thought to be due to environmental causes, perhaps in combination with genetic susceptibility factors. The overriding goal of this project is to determine the relative contributions of genetic and environmental factors in causing typical Parkinson's Disease by investigating risk factors for Parkinson's Disease in four unique populations: the NAS/NRC World War II Veteran Twins cohort (TWINS), pesticide applicators and their spouses from the Agricultural Health Study living in Iowa and North Carolina (FAME), Japanese-American men participating in the Honolulu Asia Aging Study (HAAS), and patients from the study of Parkinson's Disease Epidemiology in Kaiser Permanente Medical Care Program (PEAK). The diversity of the four populations adds great power to the investigation of environmental factors in Parkinson's Disease by increasing the likelihood that any links observed between environmental factors and Parkinson's Disease that are seen in all four populations can be generalized to the broader U.S. population. Furthermore, because methods for case definition and exposure assessment have largely been shared in these four populations, comparisons of outcomes and combined analyses are greatly facilitated. Our first specific goal is to examine the relationship between occupational exposure to toxins and the risk for Parkinson's Disease . Exposures such as agricultural work or pesticides and welding or manganese have been suggested to cause Parkinson's Disease , but definitive evidence is lacking. We are taking advantage of detailed lifetime occupational and hobby histories, rated by an industrial hygienist, to determine whether specific compounds or chemical classes cause Parkinson's Disease . Our second specific goal is to determine if habits such as the use of tobacco or caffeine protect against the development of Parkinson's Disease . Thirdly, we are investigating whether or not some individuals may have inherited changes in nerve cell function that could predispose to developing Parkinson's Disease after exposure to certain chemicals. Project 2: Neurotoxicants, Oxidative Stress and α-Synuclein in Parkinson's DiseasePrincipal Investigator: Donato (Dino) Di Monte, M.D. Animal models of Parkinson-like pathology induced by toxic compounds represent valuable tools for (i) assessing the role of environmental toxins in the etiology of Parkinson's Disease , (ii) elucidating the mechanisms that underlie neurodegeneration in Parkinson's Disease , and (iii) developing neuroprotective strategies that counteract neuronal death and could ultimately be used for therapeutic intervention in Parkinson's Disease . Our hypothesis is that nigrostriatal neurons (the neurons that undergo degeneration in Parkinson's Disease ) are particularly vulnerable to toxic agents that cause the production of harmful molecules known as reactive oxygen species (ROS). If so, environmental toxins that might play a role in Parkinson's Disease could be screened and identified based on their ability to generate ROS within the brain. Furthermore, neuroprotection could be achieved by preventing this production of harmful ROS through specific antioxidant treatment. Previous findings in our laboratory indicate that exposure of mice to the herbicide paraquat or co-exposure to aluminum (Al) plus the fungicide diethyldithiocarbamate (DDC) causes selective nigrostriatal degeneration and the formation of intracellular deposits containing the protein alpha-synuclein; this protein is a major component of Lewy bodies, which are abnormal structures/inclusions that are typically present in nerve cells in the brains of patients with Parkinson's Disease . We now plan to determine if ROS formation (i) plays a role in paraquat- and Al/DDC-induced neuronal loss, and (ii) is involved in the alpha-synuclein pathology (i.e. protein aggregation) observed after paraquat or Al/DDC exposures. Project 3: Iron, Oxidative Stress and Pesticides in Parkinson's DiseasePrincipal Investigator: Julie Andersen, Ph.D. (Buck Institute) The overall aim of our current research grant is to further our understanding of how the combination of environmental factors (such as dietary iron intake and pesticide exposure) and genetic determinates (such as those that enhance oxidative stress)) may interact to cause degeneration of the brain cells that are affected in Parkinson 's disease. We also wish to investigate these factors in the development of the intracellular inclusions in brain know as Lewy bodies. The long term goal of the studies is to identify important new clues that will lead to novel therapies for Parkinson's Disease . Project 4: Nicotine and Neuroprotection in Nonhuman Primates J. William Langston, M.D. Maryka Quik, Ph.D. An overwhelming number of epidemiological studies show an inverse correlation between smoking and Parkinson's disease; stated another way, cigarette smoking appears to reduce the risk of Parkinson's disease. Thus, in contrast to the negative effects generally associated with tobacco products, there appears to be a component in tobacco products that may actually protect against Parkinson's disease. We believe that these observations point to a novel and important research opportunity, and have made a commitment to intensively investigate this phenomenon in the laboratory with the goal of finding scientific leads that could lead to new strategies to protect against this neurological disorder. This would be most welcome as the drugs currently available for the treatment of Parkinson's disease are mainly symptomatic and are typically short acting in nature (hours). However, this task is likely to be daunting, as there are about 4000 chemicals in cigarette smoke. This will make identification of the putative "neuroprotective" component in cigarette smoke a difficult task. Because recent studies suggest that nicotine may be the active neuroprotective component in cigarette smoke, we are doing experiments with different experimental model systems to study how nicotine may reduce the occurrence of Parkinson's disease. |
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