Parkinson's Disease Department of Neurology The University of Chicago Medical Center Hospitals

 

CAUSES OF PARKINSON'S DISEASE

The cause (etiology) of Parkinson's disease is unknown. It is very likely that more than one factor contribute to Parkinson’s disease. These include the following consideration.

Environmental Exposure – Epidemiological studies have noted increased risks of developing Parkinson's disease with rural living, farming, drinking well water, and exposure to pesticides. Most of the pesticides disrupt mitochondrial function and generate oxidative stress, the two main processes implicated in degeneration of neurons. On the other hand, there have been intriguing and consistent findings of decreased risks of Parkinson's disease in people who smoke cigarettes or drink beverages containing caffeine.  We do not yet understand how to take advantage of these informations to devise therapies to stop or slow the disease progression.

Genetic Predisposition – Genetic contribution to PD has not been recognized until late 1990’s.  Only about 5-10 % of PD patients have familial aggregation of the disease and most are considered to be sporadic.  However, the family history of PD remains a strong risk factor for developing PD, suggesting that even in sporadic cases of PD, there may be susceptibility genes in an individual that make the person more likely to develop the disease.  A major step towards recognition of the genetic contribution was the discovery of a specific gene in southern European families with many members affected by the disease in 1997. A specific protein called alpha-synuclein was found to be abnormal in these patients. Although such families with alpha-synculein mutations are exceedingly rare, the same protein is involved in the pathology of PD brains in most patients, suggesting a common link between rare genetic forms and more common sporadic forms. There are about dozen genetic abnormalities that have been found to cause Parkinson's disease as of 2008.  Six of them have been identified and extensively being studied.  We are investigating how two of these genes, PINK1 and DJ-1 contribute to the development of PD.

Pathogenesis of Parkinson's Disease (the process by which dopaminergic cells degenerate)

Environmental insults, genetic abnormalities, or the combination of these trigger the processes to kill the dopaminergic neurons in Parkinson's disease.  Understanding the pathogenesis may help us to target the therapy to interrupt the disease processes.

  • Mitochondrial Abnormality – Mitochondria are the powerhouses of the cells within our bodies. They consume 90% of the oxygen within the body and are responsible for energy production and regulation of cell survival. Ongoing research suggests that patients with familial and sporadic forms of Parkinson’s disease may share mitochondrial abnormalities as a common pathway leading to cell death.

  • Oxidative Stress – In the process of normal metabolism of cells, free radicals are generated.  Free radicals are unpaired electrons that can easily react with surrounding molecules and damage them.  Perhaps of most importance, metabolism of dopamine can contribute to free radical formation, and this has contributed to the “DOPA phobia” a concept that treatment of levodopa can increase the toxic effect of dopamine and may worsen the disease.  This is very controversial without any evidence for such detrimental effect in patients.

  • Abnormal Protein Processing – Some of the genetic abnormalities that cause Parkinson's disease involves genes that are important in cleaning up and recycling proteins that are damaged in the process of normal and abnormal metabolism of the cells. In addition, many other neurodegenerative disorders such as Alzheimer's disease, Creutzfeldt-Jacob disease, and Huntington's disease show evidence of abnormalities in protein processing.

  • Inflammation – Although brain has been thought of as an immunologically privileged site, increasing number of evidences point to the role of inflammatory process in many neurodegenerative disorders including Parkinson’s disease.