Five years ago, she could
still show the world her pleasant demeanor with a smile. Four years
ago, she could no longer smile, but she was still able to walk upright.
Two years ago, she could no longer walk without aid from a walker, but
she could still find her mouth with a fork while eating dinner. Eighteen
months ago, she could no longer eat under her own power, as the involuntary
'tremors' in her hands flung the food from the fork long before it reached
her mouth. A year ago, my grandmother died. She was diagnosed
with Parkinson's Disease (PD) five years ago, and slowly deteriorated for
four years until her death. She was given myriad drugs, but none
seemed to help for more than a month, leaving her in worse condition after
the effects wore off. Herein lies the mystery of Parkinsonās Disease.
Researchers have made great progress in uncovering the etiology of this mysterious disease. Before summarizing some of the current theories on the cause of PD, however, it is necessary to describe some clinical observations of patients. Symptoms of PD include "tremors," rigidity, bradikinesia (slowness of movement) and loss of postural control (1). It has been found that patients who show these symptoms for PD have an eighty percent reduction in the levels of both dopamine (a neurotransmitter in the Substantia Nigra) and dopaminergic neurons (neurons that contain dopamine receptors) (1).
There are currently four main theories on the cause of Parkinson's Disease: (a) Oxidation of molecules such as iron in the Substantia Nigra by free radicals kill the dopaminergic neurons (1); (b) environmental toxins similar to MPTP (a compound related to the painkiller Demerol), which have been shown to cause Parkinsonism-like symptoms, kill the neurons (1,2); (c) a mysteriously increased rate of dopaminergic neuronal apoptosis in some individuals (1); and (d) Genetic influence, as the penetrance of PD has been observed at higher levels within some families (1). There is evidence for all of these theories, although the most concrete evidence comes from a study that showed increased levels of iron in the Substantia Nigra in PD patients (1). While this study proved nothing, it provided further evidence for a powerful oxidizing agent, such as a free radical, involved in the degeneration of dopaminergic neurons. The true cause of PD is most likely a combination of all four of these theories, along with revisions made by the large amount of yet undiscovered information.
There has been a great deal of research done on finding a cure for the disease, with marginal success. A drug thought by many to be a miracle drug for PD was L-dopa. L-dopa is the natural precursor for dopamine in its metabolism in the brain (which ends in the production of epinephrine). It was used as a treatment instead of dopamine to replace dopamine levels in the brain because it can cross the blood-brain barrier, and so could be applied intravenously. For a long time, L-dopa seemed to be working wonderfully, alleviating many of the symptoms of PD (3). Before long, however, it became apparent that L-Dopa was causing multiple side effects (4,5,6), including the "freezing phenomenon" in many long-term users. The "freezing phenomenon" describes a state in which the patient becomes unable to move his/her muscles (5). These side-effects resulted from the over-zealousness of researchers to find an easy answer to the Parkinson's problem. L-Dopa seemed to be a miracle drug because it erased many of the more obvious symptoms. However, it failed to make any progress in stopping the progression of the disease, and seemingly made it even worse. This evidence seems to indicate that PD may potentially be caused by an increased toxicity of the dopamine to the dopaminergic neurons, although there are no web pages to back up this hypothesis. This may be caused by any or all the pre-existing theories mentioned above. For example, take as a model someone born with a genetic predisposition to a reduced level of antioxidants (which help to eliminate free radicals). The dopaminergic neurons of this person would then have an impaired ability to rid themselves of the free radicals normally associated with dopamine metabolism. Thus, there would be a greatly increased level of free-radical dopamine metabolites, which could potentially harm the neurons. In this theory, L-dopa would actually accelerate the progression of the disease by creating even more free radicals in the Substantia Nigra, more rapidly killing dopaminergic neurons.
Other treatments are now being used, but no absolute cures have been found. Despite the long-term failure of L-dopa, it is still one of the main PD treatments. Its dosage and side effects, however, are much more closely monitored than when L-dopa was first administered. Other dopamine agonists (similar to L-dopa) are used to replace dopamine levels in the brain. None, however, have at this point been shown to work more effectively than L-dopa. Before L-dopa was discovered, surgery was used to treat PD. Recently, there has been a resurgence of surgical techniques such as Pallidotomy and Thalamotomy, in which legions are made in the patient's Globus Pallidus or Thalamus, respectively. While these surgical treatments relieve the symptoms in some patients, they are by no means universal. Experimental methods at this time include Deep Brain Stimulation, where electrodes are placed in the brain so as to stimulate the thalamus; and fetal tissue implants. Fetal tissue implants seem to show the most promise, as the fetal tissue has been shown not only to survive in the host, but to replace many of its damaged dopaminergic neurons. (7) This technique, unfortunately, carries with it a host of ethical issues, and so will most likely never become a popular treatment.
Now we are left with semi-effective treatments for Parkinsonism, all of which seem to have dangerous side effects. Why is it so difficult to find a cure for Parkinsonism? How is this disease any different than other easily treatable disorders? One factor leading to extreme difficulty in studying Parkinson's Disease is that the age of onset is generally around 50 or 60 years old. By the time patients show clear Parkinsonism symptoms, the disease has progressed far beyond its point of no return. The only move in this case would be to momentarily slow the symptomatic progression of the disease. This was exactly what L-Dopa and all of its descendants accomplished, but that is not good enough. From all of the evidence provided in this paper, it has become clear that in order to successfully treat Parkinson's Disease, one must administer a treatment near the onset of the disease, not of the symptoms. This is obviously a tricky objective, as there is yet no efficient way to diagnose this debilitating disease. This sort of treatment would require that every seemingly healthy individual in the country be tested for lowered levels of dopamine, which seems a bit impractical.
I therefore propose that a PD test be given to every newborn. Therefore, if PD begins its progression at the earlier stages of development, this test will greatly facilitate early PD studies. One potential problem with this test is that it is quite possible the onset of the disease does not occur until later in life, in which case PD tests would have to be given periodically throughout everyone's life. I realize that this solution is a bit extreme, but Parkinson's Disease leads to an extremely painful and embarrassing condition. Not only is PD such an awful disease, but it is extremely widespread, afflicting a large percentage of the population Even more widespread than the disease, however, is the interest to talk about PD, as is demonstrated by the thousands of Parkinsonism forums I came across in my search on the net (8 is an example).
Another area of study that could potentially lead to a cure is researching the genetic influence of Parkinson's Disease (9, 10). If a PD gene were found, it could lead to novel gene therapy techniques to treating the disease. As far as I could tell from my research on PD, there is not a great deal of research being done on its genetic characteristics, as the general overview web pages did not even mention genetic influence as a probable cause. There is one group of scientists, however, working in Charlottesville, Virginia, who believe they have found the gene which, when mutated, is responsible for the onset of PD (10). They performed various tests on neuronal cell lines obtained from Parkinsonās patients. They found that these neurons expressed severely depressed levels of an enzyme called complex I, the first protein in the electron transfer chain in the mitochondria. It has also been found that this lowered level of complex I leads to an increase in the level of oxygen radicals, which could easily kill off dopaminergic neurons, thus lowering the level of dopamine.
An argument against genetic inheritance of PD is that the disease seems too sporadic within families. W. Davis Parker, professor of neurology at U.Va, explains, however, that "the genes contained on mitochondrial DNA (mtDNA) exist independent of nuclear DNA. In other words, this is a new principle of human genetics that may explain why some diseases currently thought of as sporadic, like Parkinson's, may in fact be inherited in an unorthodox way" (10). Parker and his team are continuing research in order to target the specific sequence of DNA which is mutated in Parkinson's patients.
If the DNA sequence were to be found, gene therapy treatments would take off. There are various types of gene therapy, but the basic premise is that one can "trick" a cell into thinking artificially made DNA is its own. Therefore, with the knowledge of the DNA sequence, one could create, in a test tube, an unmutated complex I gene to be used for gene therapy. Since the state of the PD gene could be attained in infants, it would be possible to administer this treatment in early development, its most effective stage. Even disregarding the possibilities of gene therapy, the specific identification of the mutated nucleotides could lead to breakthrough studies on the complex I protein. Once the etiology of this mysterious disease is found, the cure is not far away.
PD research, therefore, has come a long way since the discovery of "The Shaking Palsy" by James Parkinson in 1817 (1). New, exciting treatments are produced at an ever-increasing rate. Unfortunately, a cure has yet to be found, but there seems to be a great deal of promise. If combined, the consideration of all four theories presented above (free radicals, mysterious neuronal apoptosis, environmental toxins, and genetic inheritance) could lead to even further advances in the ongoing battle against Parkinson's disease. My grandmother was a guinea pig. One can only hope that her illness provided information that brought us a step closer to a cure. Perhaps one day all of this research will pay off so that millions of elderly are spared the years of intense suffering my grandmother experienced.
1. The Parkinson's Web
2. The Parkinson's Web
neostriatal dopamine activity after intraperitoneal or intranasal
4. Novel therapeutic directions for Parkinson's disease
5. Freezing phenomenon in Parkinson disease
6. Parkinson's disease: drug therapy
7. Parkinson's Disease
8. Editorials from the Front Line
9. Familial Parkinson's Disease: A Clinical Genetic Analysis
10. Genetic Defect May Point to Heredity as a Source of Parkinson's Disease
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.