Parkinson's Disease
March 2002
WHAT IS PARKINSON'S DISEASE AND WHAT CAUSES IT?
Parkinson's disease (PD) is a slowly progressive disorder that affects movement, muscle control, and balance. Parkinson's disease is referred to as idiopathic, which means that the cause is unknown. This term distinguishes the primary disease from parkinsonism, which are the symptoms occurring from a known cause.
Parkinson's Disease and Dopamine Loss
Parkinson's disease occurs from the following process in the brain:
PD develops as cells are destroyed in certain parts of the brain stem, particularly the crescent-shaped cell mass known as the substantia nigra .


Nerve cells in the substantia nigra send out fibers to the corpus stratia , gray and white bands of tissue located in both sides of the brain.


There the cells release dopamine, an essential neurotransmitter (a chemical messenger in the brain). Loss of dopamine in the corpus stratia is the primary defect in Parkinson's disease.


Dopamine is one of three major neurotransmitters known as catecholamines, which help the body respond to stress and prepare it for the fight-or-flight response. Loss of dopamine negatively affects the nerves and muscles controlling movement and coordination, resulting in the major symptoms characteristic of Parkinson's disease.


The disease process also may impair nerve endings in the heart that regulate the release of norepinephrine, a hormone that regulates blood pressure, pulse rate, perspiration, and other automatic responses to stress. Such effects could be responsible for the abrupt drops in blood pressure when standing that some patients experience. Further research is underway to determine if the loss of nerve terminals is confined to the heart or if it affects other organs as well.
Although it is clear that dopamine deficiency is the primary defect in Parkinson's disease, it is not clear what causes dopamine loss. The culprit is less likely to be a single cause than a combination of genetic and biologic factors, which are triggered by some environmental assault.
Biologic Factors
Abnormal Apoptosis (Programmed Cell Death). In everyone, cells in the body are programmed to naturally die through a genetically regulated process called apoptosis. In Parkinson's disease, there is some evidence that this process goes awry in nerve cells.

Proteins Involved in Parkinson's Disease Important research now suggests that three molecules are critical in the development of inherited PD: parkin, alpha synuclein (specifically alphaSp22), and ubiquitin, which all interact in the normal brain. AlphaSp22 is produced in the nerve cells involved with the dopamine pathway. Parkin normally causes alpha synuclein to bind with a molecule called ubiquitin, which then triggers apoptosis causing this compound to self-destruct. In many cases of inherited Parkinson's disease, however, parkin is abnormal and fails to bind alpha synuclein to ubiquitin. Apoptosis does not take place and, instead of dying, synuclein accumulates in Lewy bodies , deposits of fibrous tissue found in all patients with PD.

Another protein that may be critical in the disease process is beta amyloid, which builds up in the brains of Alzheimer's patients and is a major factor in that disease. Beta amyloid also increases the build-up of synuclein and may help explain the connection between Alzheimer's and Parkinson's disease in many patients.

Lewy Bodies. Fibrous deposits known as Lewy bodies are the hallmark signs of Parkinson's disease. They are found in the substantia nigra, the place in the brain where dopamine is first released. It is not clear whether Lewy bodies are the major killers of the nerve cells or whether they are simply a byproduct of the degenerative process. They are found not only in the brains of patients with Parkinson's disease, but, in rare cases, may show up in cells in other parts of the body (the heart, intestine), causing severe disabling symptoms. These substances are also present in other diseases that cause dementia, such as Alzheimer's, and can occur in people without neurologic symptoms.

Complex I and Oxygen-Free Radicals. Some research has observed that certain Parkinson's patients have a 30% to 40% reduction in an enzyme called complex I. This enzyme is found in the mitochondria, sausage-like structures in cells that generate energy. Some theories suggest that low amounts of complex I may make nerve cells vulnerable to the assault of oxygen free radicals (also called oxidants). Oxidants are unstable molecules that bind to other molecules in the body. They are normally produced by the natural chemical processes in the body. If the body is subjected to environmental stresses, however, they can be over-produced. And, in access, they can damage any cell, including nerve cells in the brain, and even interferes with their DNA.

NMDA Receptors. Also of interest in PD are processes that occur in an area of the brain called the subthalamic nucleus . Here, receptors known as glutamatergic N-methyl-D-aspartate (NMDA) become persistently overexcited and produce high levels of calcium ions within brain cells. This in turn leads to a cascade of events that trigger oxygen-free radicals and cell damage.

Immune Factors and the Inflammatory Response. An over-responsive immune system triggered by initial damage may also play a role in perpetuating Parkinson's disease. When the immune system becomes over-active, it produces excessive numbers of potent factors called cytokines, which cause inflammation and further injury in brain cells. Important cytokines under investigation are interleukin-1 and tumor necrosis factor.
Genetic Factors
Specific genetic factors appear to play a strong role only in early-onset Parkinson's disease. Multiple genetic factors are likely to contribute to the great majority of Parkinson's cases, which occur in older people. Nevertheless, the study of even rare genetic cases is proving to be useful in understanding the nature of degenerative nerve diseases in general.

Early Onset PD. The cases of genetic early-onset Parkinson's disease have most often been detected in specific family groups.
Defective genes that regulate the molecules alpha synuclein and parkin, which are important in the PD disease process, may be responsible for a number of early-onset cases. [ See Biologic Factors, above.] For example, genetic abnormalities the alpha synuclein protein has been detected in some early-onset Parkinson's patients of European descent.


The parkin gene may be the cause of many cases of early-onset Parkinson's in young adults. (Parkinson's cases associated with this mutation tend to progress slowly and respond well to treatment, even after years of symptoms. Dementia is also rare with this form.)
Late Onset PD. The role of genes in late-onset, the much more common form of the disorders, is not yet clear and appears to be weak. Still, some may be important:
Research published in 2001 has targeted the gene for the tau protein, which in its healthy state is important for the support structure in nerve cells that allows the flow of nutrients through them. A defective tau gene may increase susceptibility for idiopathic late-onset Parkinson's disease.


Investigators have observed iron deposits in the brains of PD patients. Animal research suggests that genetic factors that impair iron metabolism may play a role in late-onset PD.
Environmental Assaults and Oxygen-Free Radicals
Environmental toxins, infections, and other triggers can provoke excessive production in the body of oxygen free-radicals, damaging particles that may play a major role in the deterioration of nerve cells that lead to Parkinson's.

Infectious Agents. Some research has identified immune factors that suggest a viral presence in the Lewy bodies and swollen nerve pathways of Parkinson's brains. Influenza and other potent viruses have long been known to be a cause of parkinsonism. In one well-known example, a major flu epidemic causing encephalitis in the early twentieth century left many of its victims with parkinsonism.

Environmental and Industrial Chemicals. Intense exposure to certain environmental and industrial chemicals is also being studied.


Pesticides and Herbicides. Some evidence implicates pesticides and herbicides as important factors in many cases of Parkinson's disease. A higher incidence of parkinsonism has long been noted in people who live in rural areas, particularly those who drink private well water or are agricultural workers. A large 2000 study found a strong link between high exposure to insecticides and herbicides at home and a 50% to 70% increase in risk of Parkinson's. Important studies are implicating rotenone, a common organic chemical in pesticides, which may release powerful destructive oxidants that target the dopamine nerve cells that are important in PD. Rotenone is very unstable, however, and some research suggests that it becomes inactive too quickly to affect human brains.


Other Chemicals. Intense exposure to other industrial chemicals and metals (manganese, copper, lead, iron, mercury, zinc, aluminum, and others) has also been linked with parkinsonism, which is often reversible. The role of long-term exposure in the development of Parkinson's disease is unclear.
Aging Process
Most, but not all, Parkinson's victims are elderly. Some studies indicate that the very elderly are not susceptible to the disease, indicating that the aging process itself is not the major player in the disease. Aging does appear to reduce the concentration of dopamine in structures called dopamine transporters, which carry the neurotransmitter back and forth between nerve cells. Some researchers posit that any excessive stress on these transporters might trigger Parkinson's disease in the aging, and more vulnerable, brain.


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Definition and Causes of Parkinson's Disease, Symptoms, Risk Factors, Severity and Outlook, Diagnosis, Guidelines for Treating the Stages of Parkinson's Disease, Levadopa (L-Dopa) Treatment, Other Drug Treatments, Surgical Procedures, Lifestyle Changes, Support Organizations

©2002 A.D.A.M., Inc. (or its subsidiaries)