Executive Summary

Like most diseases, Parkinson's Disease (PD) appears to arise from the interaction of three events - an individual's inherited genetic susceptibility, their subsequent environmental exposures, and their age. Limited research has been done on identifying both the environmental and genetic interactions that are likely to lead to PD. We clearly need to intensify efforts to understand the environmental triggers of this disease, the importance of the timing of exposure to these triggers in influencing disease development, and the interplay between these exposures and a person's underlying genetic constitution and susceptibilities. This knowledge, once generated, will lead to better detection of the earliest stages of PD development, to improved therapeutics, and, most importantly, to viable prevention strategies so that people need not suffer from environmentally-caused PD.

Many promising lines of investigation are already supported by the National Institute of Environmental Health Sciences (NIEHS) and other public and private organizations. In order to further enhance the field, NIEHS held a workshop to identify research opportunities and needs, developed a joint Request for Applications (RFA) with the National Institute of Neurological Disorders and Stroke (NINDS) to recruit more scientists into investigating environmental components of PD, and established a mechanism to increase the pool of physicians engaged in understanding the environmental underpinnings of PD. The NIEHS has also lead a trans-National Institutes of Health (NIH) initiative to define how environmental toxicants cause cell injury and death and how this injury can develop into neurodegenerative diseases such as PD. This document summarizes current research activities supported by the NIEHS and describes new initiatives in this field. For more information on PD and other aspects of the NIEHS research portfolio, please visit the Institute's web site at www.niehs.nih.gov.

Introduction

What is Parkinson's Disease?

Parkinson's Disease (PD) is a nervous system disorder. The primary symptoms are: (1) tremor or trembling in hands, arms, legs, jaw, and face, (2) rigidity or stiffness of the limbs and trunk, (3) bradykinesia or slowness of movement, and (4) postural instability or impaired balance and coordination. As these symptoms become more pronounced, patients experience difficulty walking, talking, or completing even simple tasks.

Parkinson's Disease (PD) is the second most prevalent neurodegenerative disorder after Alzheimer's Disease. Most cases begin after the age of 50 and its incidence increases as a function of age. Almost 50,000 Americans are diagnosed with PD each year, with an estimated cost to this nation of $5.6 billion annually.

What is Known about the Basic Biology of Parkinson's Disease?

At the cellular level, PD is characterized by cell loss in a specific region of the brain (substantia nigra) that modulates movement. This cell loss results in the loss of the biological function of these cells, which is to produce the neurotransmitter, dopamine. Dopamine controls signaling to the region of the brain (motor cortex) responsible for initiating smooth movement. Thus lower dopamine levels lead to the jerky, uncontrolled movements characteristic of PD.

Although dopamine loss underlies the pathophysiology of this disease, postmortem examinations of PD patients have revealed that another change also occurs. PD patients develop microscopically visible structures called Lewy bodies (LBs), the significance of which is still being studied.

What are the Risk Factors for Parkinson's Disease?

A number of factors, both environmental and genetic, have been identified as being associated either with development of PD or with a reduced risk for developing PD.

• Genetic Factors: The relevance of genetic contributions to PD was the topic of a recent study by Dr. Caroline Tanner at the Parkinson's Institute and her colleagues. In this study of monozygotic (identical) and dizygotic (fraternal) twins, researchers found that when one twin had early onset PD, the other twin was much more likely to also develop PD if the twins were identical. One can conclude, therefore, that genetic susceptibility played a significant role in PD when symptoms are seen prior to age 50. In the vast majority of cases, though, where PD develops after age 50, the twins of PD patients were found to also have PD rather infrequently, regardless of whether the twins were identical or fraternal. For the more common, late onset PD, genetic contributions are likely to be less obvious and more difficult to identify, either because susceptibility genes have weaker effects or their effects are obscured by the long time course for developing the disease. Presumably other factors, such as environmental exposures or random cellular events that occur during aging, play a much more important role in promoting the development of late-onset PD than they do in early onset PD.

• Environmental Factors: Important insights into environmental triggers of PD were gained in the early 1980s when a synthetic heroin elicited severe Parkinsonism in addicts who injected it intravenously. The initiating agent was found to be a contaminant, 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP), a compound with structural similarities to some herbicides and pesticides. Subsequent studies have found increased incidence of PD associated with exposures to pesticides, heavy metals, and solvents.

  Environmental exposures should not only be thought of as single compounds. NIEHS-supported scientists found that exposure to a mix of agricultural compounds (paraquat and maneb) decreased motor activity, increased dopamine turnover, and reduced other measures of dopamine effect at levels far greater than when the same chemicals where administered singly. The fact that combined exposures, such as would be found in "real-world" applications, can greatly enhance the adverse effects on the dopamine system raises important possibilities for multiple environmental risk factors being associated with PD development.

  Another group of NIEHS-supported researchers examined groups of people occupationally exposed to heavy metals and found that exposures to combinations, rather than single compounds, were associated with increased risk of developing PD. In this case it was mixtures of lead, copper, and iron that posed a greater risk than did exposure to these metals singly.

  Other environmental factors that increase risk are viral infections, such as encephalitis, and head injuries. Interestingly, there are also environmental factors that might decrease risk to PD. These include tobacco smoking and dietary antioxidants.

What is the Future of PD Prevention Research?

Like most diseases, PD appears to arise from the interaction of three events - an individual's inherited genetic susceptibility, their subsequent environmental exposures, and their age. Much research has been done on identifying genetic contributions to PD. Clearly we now need to intensify efforts to understand the environmental triggers of this disease, the importance of the timing of exposure to these triggers in influencing disease development, and the interplay between these exposures and a person's underlying genetic component. In fact the timing of exposures might be critical in understanding the environmental components of PD. It has been suggested that PD requires an initial "hit" of a toxicant on vulnerable genes, which then render an individual sensitized in a way that makes them more susceptible to subsequent environmental "hits" at low doses that would otherwise be safe. Another scenario that could increase susceptibility would be when an individual is exposed to a chemical mixture, in which one of the components reduces the ability of the body to protect itself against other components of the mixture. This could occur, for example, if an environmental toxicant caused oxidative stress that reduced the brain substantia nigra cells' ability to produce glutathione which is necessary to protect these cells from the damaging effects of hydrogen peroxide. The subsequent cell injury and death arising from a complex exposure could set in motion the cascade of events that lead to PD.

Equally important is to follow-up on how certain environmental components, such as tobacco smoking and antioxidants, reduce risk to PD. We are also at a stage where we could develop biomarkers that identify all forms of PD and could be used in studies to track the onset and progression of this disease, as well as evaluating treatment success.

These promising lines of investigation are already underway by NIEHS-supported grantees. In order to further enhance the field, NIEHS held a workshop to identify research opportunities and needs, developed a joint Request for Applications (RFA) with the National Institute of Neurological Disorders and Stroke (NINDS) to recruit more scientists into investigating environmental components of PD, and, through another RFA, established a mechanism to increase the pool of physicians engaged in understanding the environmental underpinnings of PD. This document will briefly summarize current research activities supported by the NIEHS, will give a synopsis of the national workshop on environmental components of PD, and will describe the new initiatives in this field.

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Page created: Jan 2003 | Content Reviewed: 14 Apr 2003
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