This paper reflects the research and thoughts of a student at the time the paper was written for a course at Bryn Mawr College. Like other materials on Serendip, it is not intended to be "authoritative" but rather to help others further develop their own explorations. Web links were active as of the time the paper was posted but are not updated.
2001 Second Web Report
The first step in linking changes in the brain to Parkinson's behavior occurred in the early 1900's with autopsies performed on people who suffered from the disease (2). Such procedures revealed significant cell death in the midbrain - - more specifically of pigmented cells that are collectively known as the substantia nigra ("black substance," named for the presence of melanin). Because damage to the substantia nigra resulted in impaired motor control, it was logically hypothesized that this area played a role in the control of movement.
With the knowledge that neurotransmitters were the means of communication for the nervous system, autopsy testing in the 1950's of Parkinson's patients showed that dopamine levels in an area adjacent to the substantia nigra, known as the striatum, were only about 10-20% of the levels present in unaffected individuals (3). The parallel of the low level of dopamine and the death of cells of the substantia nigra in Parkinson's patients led scientists to postulate that the substantia nigra produces dopamine. When levels were disrupted due to cell death, this would likely lead to a change in stimulation in this area of the brain, which would produce behavior characteristic of Parkinson's.
Anatomical research since then has shown that the substantia nigra is part of the basal ganglia, whose other components include the globus pallidus, subthalamic nucleus, and striatum (3). Through experimentation, a series of nerve signal pathways have been mapped out which help us to understand how this region of the brain functions to control movement. It has been hypothesized that cells of the frontal cortex initiate signals for movement (4). (It was concluded that the basal ganglia does not initiate movement because damage to this area as occurs in Parkinson's still allows for voluntary movement; if it were responsible for its initiation, the damage would likely inhibit voluntary movement.) The frontal cortex sends its signals to the basal ganglia, which, through a series of pathways, fine tunes movements in terms of fluidity, speed, reaction time, and its beginning and ending. (This was concluded because although voluntary movement can be achieved in Parkinson's patients, the movement is characterized by sluggishness and a lack of coordination.) The low level of dopamine in the striatum alters the pathway such that the normal response of balance and coordinated movement is not achieved (2). Involuntary movement, such as tremors, may be accounted for by the fact that the lack of dopamine appears to cause neurons in the basal ganglia to fire randomly; thus, the basal ganglia would be unable to inhibit involuntary movement.
In order to alleviate the symptoms of Parkinson's, it became necessary to find a way to deliver dopamine to the brain in order to compensate for its falling levels. Unfortunately, dopamine cannot be directly administered because it is unable to cross the blood-brain barrier (3). Therefore, the synthetic pathway of dopamine was studied in an effort to find another way to introduce dopamine to the body. Scientists have hypothesized that dopamine is derived from the amino acid tyrosine (3). With the aid of the enzyme tyrosine hydroxilase (TH), tyrosine is converted to L-DOPA, which is in turn converted to dopamine by the enzyme 1-amino acid decarboxylase (AADC).
Based on this proposed synthetic pathway, scientists attempted to manipulate the nervous system in order to return it to its normal state of function by looking for a way to indirectly introduce dopamine into the system. The discovery that L-DOPA is able to cross the blood-brain barrier proved to be an effective treatment as this precursor can be transformed into dopamine (3). While intake of L-DOPA reduced the severity of Parkinson's symptoms, suggesting that it was effectively transformed into dopamine, it also caused severe side effects such as nausea, vomiting, and altered blood pressure. Investigation into these problems revealed that the enzyme AADC (which converts L-DOPA into dopamine) is also present in areas of the body other than the brain, such as the liver and kidneys. Labelling of L-DOPA showed that only about 1% of the L-DOPA reached the brain, while the other 99% went to the GI tract (5). Therefore, scientists concluded that while the levels of dopamine returned to normal in the striatum, the levels climbed to above-normal in these other parts of the body, resulting in the side effects. As a result of this observation, scientists developed the AADC inhibitors that cannot pass the blood-brain barrier. This allowed for dopamine levels to increase in the brain, but not to become elevated in other organs and thus largely eliminated the negative side effects (3). L-DOPA taken simultaneously with AADC inhibitors remains one of the most effective drugs in treatment of Parkinson's symptoms.
Because of the success of patient response to L-DOPA treatment - - particularly when taken with AADC inhibitors - - the hypothesis that Parkinson's is a consequence of a decreased level of dopamine in the brain is bolstered. Because there is no test available for Parkinson's disease (such as a blood test or X-ray to distinguish it from other neurodegenerative diseases), the administration of L-DOPA has become the "test": if a patient responds to the drug, he is diagnosed with Parkinson's (6).
Unfortunately, L-DOPA and other Parkinson's drugs are only able to control the symptoms of the disease and are not a cure. Recently, doctors have attempted to transplant fetal cells (specifically the precursors of basal ganglia cells) into the striatum in the hope of regenerating the substantia nigra and thus replenishing the brain's natural supply of dopamine (6). However, the studies performed by Genzyme Corporation and Diacrin Inc. have not given the results hoped for (7). Although the fetal cells reproduced and raised levels of dopamine in the brain, the increase in levels was too dramatic and resulted in unreversible uncontrolled limb movement (8). It is hoped that alterations to the procedure performed will give better results.
The cause of the degeneration of the cells of the substantia nigra has not yet been determined, and thus doctors can only alleviate a patient's symptoms of the disease rather than attempt to reverse its course. Research has suggested that Parkinson's may be caused either genetically or through an environmental toxin.
The "Parkin" gene, which is found on chromosome 6, plays an important role in the destruction of proteins that do not function properly - - due to age or malformation (9). It is necessary that such proteins be broken down because they are known to be oxidized to toxic free radicals that accumulate in cells if they are not. The parkin protein (coded for by the Parkin gene) works with the molecule ubiquitin to tag such defective proteins for destruction. It is believed that the mutated parkin protein tags damaged proteins at a slower rate, which results in the accumulation of toxic free radicals in cells, thus leading to death of the cells of the substantia nigra. Based on a sampling of Parkinson's patients, it has been estimated that the mutated form of the Parkin gene is found in approximately 25% of those afflicted with the disease. Another gene that codes for alpha-synuclein, a protein of unknown function, has also been implicated in causing Parkinson's disease (9). The aging form of this protein has been shown to be broken down at a lower than normal rate and subsequently accumulates in cells. This protein accumulation may be a component of the Lewy bodies that are found in the brains of a fraction of Parkinson's patients amongst the dead cells of the substantia nigra (pesticides).
Because defective genes are only found in a percentage of Parkinson's patients, scientists have been looking for other causes. The discovery that the chemical MPTP appeared to cause Parkinson's in drug users by inhibiting complex I of the electron transport chain in the mitochondria of nerve cells had an important implication: the common pesticide rotenone is also an inhibitor of complex I (10). Chronic exposure to such a chemical may lead to the onset of Parkinson's. Geographical studies have been performed which indicate a higher incidence of the disease in rural areas where one would expect pesticides to be used (6). While the pesticide may be a possible cause of the disease, we must consider the fact that because Parkinson's existed well before the use of pesticides became common, there are other more significant causes.
Parkinson's was once a scientific mystery that could only be described as "the shaking palsy." The scientific method has enabled neuroscientists to examine the pathology of Parkinson's by first proposing a hypothesis, testing it, and subsequently revising their theories based on experimental results. Scientists first determined the affected area of the brain, then examined its role and finally designed treatment to alleviate symptoms. The use of this "reverse approach" in understanding the disease is sound scientific methodology, the validity of which is hard to question. Research in the field of Parkinson's has further recognized the complexity of the nervous system in that a change at the neuronal level clearly affects parts of the brain and thus the behavior of an individual. While there are many aspects of Parkinson's that we still do not comprehend, such as its causes, the further step-by-step analysis of neuroscientists will allow us to become progressively "less wrong" about its pathology.
2)Parkinson's Information , This site is good for the basic neurobiology of Parkinson's (complete with diagrams) and descriptions of drugs
3)The Dopamine Theory of Parkinson's Disease, This was the best site I found with a description of the synthetic pathway of dopamine, neuronal pathways in the brain, and the drugs used for treatment.
4)The Michael J. Fox Foundation for Parkinson's Research, This site has a basic explanation of the pathology of Parkinson's
5)Parkinson's Disease, This is a good website for those with a good background in neurobiology for information on Parkinson's
6)Young Parkinson's Handbook, This is a exhaustive handbook for people afflicted with the early onset form of Parkison's
7) "Setback in Treatment for Parkinson's" , This is a New York Times article about the recent problems with fetal tissue transplants
8) "The Arrow of Progress", This is another New York Times article about recent problems with fetal tissue transplants
9)Genes and Parkinson Disease, This is part of the National Parkinson Foundation web site with information about the possible genetic cause of the disease
10)Pesticides and Parkinson Disease, This is part of the National Parkinson Foundation web site with information about the possible environmental cause of the disease
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