Parkinson's Disease Research
Parkinson's disease (PD) is a progressive degenerative disease of the central nervous system, affecting individuals in adult life. It is a chronic condition that usually develops in people over the age of 50, and there are around 50 000 new cases each year in the United States. The pathology is a specific pattern of nerve cell (neuronal) degeneration in a region of the brain called the substantia nigra, as well as in other regions that control movement. It creates a shortage of the brain-signalling chemical (neurotransmitter) known as dopamine, resulting in impaired movement. Degenerating neurones in PD characteristically deposit intracellular structures known as Lewy bodies, thought to be altered cytoskeletal elements, which accumulate due to neuronal damage. The symptoms of PD include slowness of movements and reflexes (bradykinesia), muscular rigidity, resting tremor and difficulty with balance and walking. There is at present no specific biological test for the diagnosis of PD, and cases are frequently confirmed at autopsy. Despite its importance and severity and the many years of research, a cause has not yet been identified and there is, at present, no means of preventing PD, nor any proven permanent cure. Current treatment relies on symptom alleviation through drugs or surgical intervention.
One important aspect of current research into PD is an attempt to find a genetic link by means of population studies. A genetic link has been suspected for some time, but studies with twins have shown variable results, and suggest that the genetics of this disorder is quite complex. The disease is presently divided into sporadic PD and familial PD because of the apparent lack of any single, underlying genetic cause. Most cases of PD appear to be sporadic as are cases of several other neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS) and Alzheimer's disease. However, in many of these, multiple gene loci have been found which might give patients a predisposition for such diseases. Recently, familial PD was recognized to be more frequent than was previously thought, and some physicians say that PD is more prevalent in clinical practice than familial Alzheimer's disease or familial ALS.
Research into familial PD focuses on special populations of families. These can include families with many affected members, those that are geographically restricted, families in which the origin of the disorder can be traced back to a single individual, or those that have an early age of onset or unusual severity. Through linkage and allele sharing analysis, attempts are being made to locate genetic markers and also to determine the probability of penetrance, i.e., calculate the proportion of individuals who manifest such markers at the phenotype level. There are also efforts being made to identify the genes that increase the risk for the disorder. Aspects of interest include the determination of possible genetic heterogeneity and any evidence of multifactorial inheritance with environmental interaction. It is believed that if genetic factors for PD susceptibility are found, they will enhance epidemiological studies and might lead to the identification of susceptible groups or significant environmental risk factors. The difficulties in this work are that the signs and symptoms of familial PD do not differ from sporadic cases. They are also heterogeneous in onset and course, and wide variations of expression occur within families. The analysis of data from this research has so far shown some large families in which autosomal dominant inheritance with high penetrance is apparently demonstrated. In contrast, in small multicase families, the inheritance pattern is compatible with either autosomal dominance with reduced penetrance or multifactorial inheritance. The apparent paucity of parental consanguinity indicates no recessive inheritance, and X-linked inheritance is also thought not to be involved in PD.
There is also some evidence for possible environmental causes for PD. These have emerged from studies in humans and animals subjected to the neurochemical methylphenyltetrahydro-pyridine (MPTP). MPTP is broken down by the enzyme monoamine oxidase B into MPP+, which significantly interferes with the function of the mitochondrial respiratory chain and ultimately results in the death of neurones producing dopamine. From this, it appears that mitochondrial dysfunction may also play a role in the clinical presentation of PD.
Another important area of PD research is in improving methods of treating PD. Medical administration of the missing neurochemical dopamine is ineffective since it apparently does not enter the brain from the blood. Instead, a metabolic precursor of dopamine, L-DOPA, is used which can diffuse into the brain where it is converted to dopamine. PD is therefore most commonly treated with pharmaceutical products containing L-DOPA, but in more advanced cases neurosurgical procedures have to be used. With the advent of gene therapy, there is now hope that this will provide a feasible alternative for the long-term treatment of PD. Animal models have shown promising results with the long-term production of L-DOPA following just a single gene therapy treatment. Adeno-associated viral (AAV) vectors have been used to deliver two human genes to the specific area of the brain affected by the disease in PD rat models. Following gene transfer, the chemical synthesis of L-DOPA was demonstrated and the expression of the L-DOPA producing enzyme was stable for one year, throughout the duration of the study. There were no observable toxicities after treatment, and importantly, there were no other regions of the brain affected by the gene delivery. Thus, gene therapy may yet prove to be the most effective way of treating PD in the future.
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