Nine Scientific Pathways to Understanding Parkinson ’s

Scientists generally agree that Parkinson’s disease is likely to be “multi-factorial” – this is, it has a variety of causes. These may include genetic factors (the inheritability of PD), the environment (e.g. toxins), the effects of aging and possibly viral or bacterial infections or other life stressors. Over the past five years, we have seen major advances in understanding the condition. There are at least nine, interrelated scientific theories about the chain of events that are thought to determine and influence the development of PD. In no particular order of importance or plausibility, these are as follows: genetic factors; protein misfolding and aggregation; oxidative stress; excitotoxicity; mitochondrial impairment; microglial activation; loss of trophic factors; over-activity of basal ganglia output; and apoptosis.

1. Genetic Factors

   In these past five years, a total of 10 genes or gene loci have been linked to PD. Dr. John Hardy, a geneticist at National Institutes of Health (NIH), told the scientists who were gathered in January, 2000 to formulate the NIH’s PD Research Agenda: “it all starts with the strings,” that is, the DNA strings that comprise our genes. Only a few families have a genetic form of PD. But research on these families can provide a window on the mechanisms and help to answer what causes the common form of PD. The study of genetic forms of PD also helps elucidate disease pathways and potential points of treatment.

   In a few, very rare, families, the development of PD is caused by a genetic change in alpha synuclein. This type of PD - very early in onset and fast progressing – is different from the usual form of the disease.

2. Protein Aggregation (abnormal “clumping” of proteins)

   A growing number of studies have suggested that in PD, alpha-synuclein becomes misfolded and tangled. Scientists have also noted that the alpha-synuclein protein is found in small clumps together with other proteins in the brains of Parkinson’s patients and form inclusions known as Lewy bodies. The same pattern of abnormalities in proteins has also been found in people with Alzheimer’s and some other neurodegenerative disorders.

   So what does this mean for people with Parkinson’s? If protein aggregation is the problem, how do we inhibit or “disaggregate those aggregates”? Scientists are looking at ways in which our bodies could be instructed to increase the quantity of proteins whose natural function is to clean up these clumps and unwanted proteins. There are already some agents on the market that exhibit this property, although they are used for different purposes —for example, an ulcer medication in Japan.

   Heavy metals and pesticides have already been linked to PD. Both metals and pesticides in these studies have also been found to accelerate the clumping of alpha synuclein, presenting what is perhaps corroborative evidence.

3. Oxidative Stress and Dopamine Transport

   In the brains of people with PD, dopamine gets trapped inside the cell structure, unleashing oxidants that need de-toxing by antioxidants to prevent damage to the neurons. DJ-1, the most recently discovered Parkinson’s disease gene, is thought to protect the body from oxidants. A few rare PD families have been found with changes in this gene that seem to support this finding.

4. Excitotoxicity

   GABA and glutamate, respectively, are “inhibitory” and “excitatory” neurotransmitters in the brain. In a PD brain, they get out of balance. Correcting the abnormal balance may be neuroprotective. This correction may be pursued surgically, through gene therapy, or pharmacologically.

5. Mitochondrial Impairment

   The mitochondria are small bodies within cells that produce energy. Simply viewed, they are the ‘powerhouse of the cell’. Deficiencies in mitochondrial function may play a role in PD. This phenomenon has been observed in research studies: when rats are made parkinsonian by feeding them rotenone a common pesticide, there is a reduction in the mitochondrial function.

   These studies are instructive both in that they seem to implicate mitochondria in Parkinson’s and in what they suggest about therapeutic interventions that could strengthen mitochondrial function.
   
   The entire workings of our body are dictated through the genes that we inherit. Thus, our ability to produce energy (through genetic heritage), together with whether we are exposed to pesticides such as rotenone, may determine whether we develop PD or not. This is a classic example of the environment and genes coming together to determine our health.
   
   
6. Microglial Activation

   Microglial cells are small non-neural cells that form part of the supporting structure of the central nervous system. When stimulated, these cells promote an inflammatory response and they can secrete toxic substances that may induce cell death.

   Minocycline, an antibiotic, may act to inhibit microglial activity. It has had some success in animal models of both PD and Lou Gehrig’s Disease. Anti-inflammatory agents have also been shown to reduce microglial activation and to protect against degeneration in an animal model. In addition, there are some over-the-counter anti-inflammatory treatments that may be of therapeutic benefit.

7. Loss of Trophic Factors

   It is clear from nonhuman primate and human transplant studies that merely replacing dopamine cells (through fetal transplant grafts) is not sufficient to assure that they will flourish in their new environment. Scientists are accordingly looking for ways of supporting them with growth, or “trophic” factors that will keep them functioning. Aged brains have reduced levels of growth and regenerative factors than younger ones. Thus, grafts in older rats show lower survival rates. But there is evidence that use of trophic factors promote graft survival. Identifying the factors that will promote growth is crucial to this research.

8. Abnormal Output from the Basal Ganglia

   Reduced levels of dopamine cells in the nerve pathway from the substantia nigra (the area within the basal ganglia where cells manufacture dopamine) in turn correlates with decreased motor function and increased neuronal output from an area known as the global pallidus. This abnormal “firing” explains the sleep problems many PD patients experience.

   Lesions or inhibition of this area can interrupt the exaggerated output. For several years, neurologists have been using interventions such as the surgical technique known as deep brain stimulation (DBS) to halt the abnormal output of neurons and ease the symptoms of PD.

9. Apoptosis

   Apoptosis is a pattern of cell death affecting single cells. While cell death is a natural process, in cases of PD it seems to go overboard. Scientists are trying to stop cells descending to a premature or unnatural fate through interventions such as the use of ‘caspase inhibitors’ that can stop activation of the lethal pathway. Another possible intervention could be by the injection of growth factors. Scientists warn, however, that some modes of interrupting apoptosis could be potentially dangerous and carcinogenic.

The above account might leave the impression that each of these proposed mechanisms is a stand-alone theory. In fact, the causation of PD is likely to involve complex interactions among several of these mechanisms; when the PD process gets underway, it is probable that multiple things go wrong. Thus most of these so-called mechanisms may reflect particular aspects of a disease process in which there are many variables.

This brief review was inspired by a section on scientific opportunities that appears in a larger and more comprehensive paper on Parkinson’s advocacy written by Jeffrey Martin Esq., Chair of the Parkinson’s Action Network.