Nicotinic receptors, smoking and Parkinson's Disease
Initial Award Abstract
Parkinson’s disease (PD) is one of a few conditions in which cigarette smoking appears to decrease the risk of developing the disease, with a reduced risk of 50% among ever smokers compared to never smokers. Despite the fact that this reduced risk among cigarette smokers has been consistently observed in studies conducted over the past several decades, there has been very little epidemiologic research to investigate the possible explanations for this apparent protective effect. This effect could play a very important role in preventing the development of PD, which is thought to be caused in part by exposure to environmental chemicals such as pesticides or metals. A number of chemicals in tobacco products could explain why smoking decreases the risk for PD, and recent laboratory studies suggest that the nicotine in tobacco products may play a role. The brain contains several different types of receptors for nicotine (called nicotinic receptors), and some are found in the basal ganglia, the area of the brain affected by PD. Dopamine is the brain chemical in the basal ganglia that is depleted in patients with PD, causing symptoms of a shuffling walk, slow movements, tremor, and difficulty controlling movement. Animal studies have shown that the nicotine from cigarette smoke stimulates nicotinic receptors, which in turn could interfere with the dopamine cell loss caused by environmental chemical exposure, or to enhance the release of dopamine, the brain chemical that is deficient in PD. The structure of the nicotinic receptors may be different among different individuals due to genetic differences in how nicotinic receptors work.
Our epidemiologic study will determine whether genetic variants of the nicotinic receptors explain the reduced risk of PD that is observed with cigarette smoking. This study will include 750 people that are newly diagnosed with PD newly diagnosed PD patients (cases) and 750 people without PD (controls) from case-control study conducted within the Northern California Kaiser Permanente Medical Care Program. We will collected a detailed lifetime history of cigarette smoking, along with other factors that may influence the risk of PD (e.g., exposure to pesticides and metals in the workplace and home, alcohol use, recreational drugs, medications, hormonal factors, family history and others). By combining a laboratory-based study of the nicotinic receptor genes with detailed information from PD cases and controls regarding cigarette smoking and other factors, we hope to understand why cigarette smoking reduces the risk of Parkinson’s disease. Ultimately, if the reasons for the protective effect of tobacco exposure were understood, tremendous gains in understanding the cause of PD could emerge and treatments could be developed to prevent or reduce the significant limitations caused by this disease. |