What causes Parkinson's disease?
The immediate cause of Parkinson's disease is degeneration of brain cells in the area known as the substantia nigra, one of the movement control centers of the brain. Damage to this area leads to the cluster of symptoms known as "parkinsonism." In Parkinson’s disease, degenerating brain cells contain Lewy bodies, which help identify the disease. The cell death leading to parkinsonism may be caused by a number of conditions, including infection, trauma, and
poisoning. Some drugs given for psychosis, such as haloperidol (Haldol) or chlorpromazine (thorazine), may cause parkinsonism. When no cause for nigral cell degeneration can be found, the disorder is called idiopathic parkinsonism, or Parkinson's disease. Parkinsonism may be seen in other degenerative conditions, known as the "parkinsonism plus" syndromes, such as progressive supranuclear palsy. The substantia nigra, or "black substance," is one of the principal movement control centers in the brain. By releasing the neurotransmitter known as dopamine, it helps to refine movement patterns throughout the body. The dopamine released by nerve cells of the substantia nigra stimulates another brain region, the corpus striatum. Without enough dopamine, the corpus striatum cannot control its targets, and so on down the line. Ultimately, the movement patterns of walking, writing, reaching for objects, and other basic programs cannot operate properly, and the symptoms of parkinsonism are the result.
It is possible that early exposure to some as-yet-unidentified environmental toxin or virus leads to undetected nigral cell death, and that Parkinson’s disease then becomes manifest as normal age-related decline brings the number of functioning nigral cells below the threshold needed for normal movement. It is also possible that, for genetic reasons, some people are simply born with fewer cells in their substantia nigra than others, and they develop Parkinson’s disease again as a consequence of normal decline. As of 1998, however, no gene or toxin had been identified to explain the large number of cases of Parkinson's disease seen each year. 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. 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. Some evidence implicates pesticides and herbicides as important factors in many cases of Parkinson's disease. 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.
Much research has gone into identifying the cause of Parkinson’s disease, but to date no culprit has been found. While both genetic and environmental factors have been investigated, no clear candidate has emerged. There are some known toxins that can cause parkinsonism, most notoriously a chemical called MPTP, found as an impurity in some illegal drugs. Parkinsonian symptoms appear within hours of ingestion, and are permanent. MPTP may exert its effects through generation of toxic molecular fragments called free radicals, and reducing free radicals has been a target of several experimental treatments for Parkinson’s disease using antioxidants. There may be a hereditary tendency to the disease that is worsened by factors in the environment. Some people with Parkinson's disease have an abnormality on chromosome 4. 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. Defective genes that regulate the molecules alpha synuclein and parkin, which are important in the Parkinson’s disease 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.)
The mechanism by which the brain cells in Parkinson's are lost appears to center on an abnormal accumulation of the protein alpha-synuclein in the damaged cells. This protein forms proteinaceous cytoplasmic inclusions called Lewy bodies. The precise mechanism whereby aggregates of alpha-synuclein damage the cells is not known. The aggregates may be merely a normal reaction by the cells as part of their effort to correct a different, as-yet unknown, insult. It does appear that alpha-synuclein aggregation is enhanced by the presence of dopamine and the byproducts of dopamine production. 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. Parkinson’s disease 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.
A number of drugs taken for long periods of time or in excessive dosages can cause symptoms of Parkinson's disease. These include medications such as haloperidol (Haldol) and chlorpromazine (Thorazine), which are prescribed for certain psychiatric disorders, as well as drugs used to treat nausea, such as metoclopramide (Reglan) and prochlorperazine (Compazine). The epilepsy drug valproate (Depacon) may also cause some of the features of parkinsonism, especially severe tremors.