At the 2012 Annual Meeting of the American Academy of Neurology (AAN) in New Orleans, Louisiana, Dr. Caroline Tanner received the Movement Disorder Research Award and presented new data on the etiology of Parkinson disease (PD). Medscape sat down with Dr. Tanner the following morning to discuss her work, the evolving understanding of PD etiology, and therapeutic approaches with the potential to -- finally -- prevent PD.
What Causes Parkinson Disease? Introduction
Medscape: What is currently known about the etiology of PD, and what genetic and environmental factors are thought to play a role?
Dr. Tanner: I think there certainly are 2 factors at work: genetics and the environment. This becomes more and more interesting as time goes on, as we recognize the many different types of interaction between genes and environment.
Classic examples involve the combination of an inherited metabolic characteristic, such as a detoxification enzyme, and exposure to a toxicant that is metabolized by that enzyme. Individuals who are genetically poor metabolizers are more vulnerable when exposed to the toxicant. In recent years, scientists have recognized other interactions. For example, epigenetic changes, such as methylation affecting gene function or replication, could be caused by environmental exposures.
So it's interesting to see how much both genetics and environment matter. At this point, it's hard to say whether genetics or environment is more important, because I don't think we have enough information yet to be able to tell completely.
We know that there are very rare forms of PD that are strongly genetically determined. There are a few genes that are almost 100% penetrant, such as the dominantly inherited mutations in the alpha-synuclein gene. But these are pretty rare and are only seen in a few families here and there, usually those with Mediterranean lineage. But recognizing these forms was really important.
Since recognizing the alpha-synuclein point mutations, we began to notice that other changes in the gene may also influence PD risk; people who have duplication or triplication of the normal nonmutated gene may also develop PD. Clearly, this tells us that alpha-synuclein protein is important in PD pathogenesis. And then, people noticed that changes in the promoter region of this gene could also affect risk, but in this case the genetic change just serves as a risk factor.
We've just recently published an example of gene/environment interaction involving the promoter region of the alpha-synuclein gene. We have known for years that head injury is associated with a greater risk for PD, but not all people with head injuries develop PD. Our recent work, presented by my colleague Sam Goldman, provides an explanation. Depending on your promoter region variant, your vulnerability to getting PD if you have a head injury varies. This is one example of the combined effects of genotype and environment on PD risk.
I think the more we look, the more we're going to find. I think that almost everything we end up calling a "risk factor" as far as genes go is likely to also have environmental influences that will determine whether or not PD develops. Similarly, for almost every environmental factor, I think the underlying genetic substrate is important. And it gets more complicated: For many people, there may be multiple genes and multiple environmental factors working together to cause PD, and an individual person's risk will be due to the combined effects of all of these influences.
Medscape: So one day, we could be saying, for example, that a patient has "x" mutation that puts them at an elevated risk for PD, coupled with a known environmental exposure, and therefore they have a certain calculated risk for PD?
Dr. Tanner: Yes. I do think with the current state of information processing, it will be possible to come up with a risk quotient. But that's a bit far into the future. People are already more or less doing this for other complicated diseases, such as heart disease and diabetes. We tend not to think about this approach in terms of PD, but if you told someone that their stroke risk depends on both their genes and their environment, they'd probably say, "Sure." This is still a relatively new idea in PD. But we're getting there.
The other important direction for research is to investigate the extent to which certain risk factors might be easily modifiable. It's just like with stroke or heart disease: If exercise makes a positive difference in PD, as data presented at this week's meeting showed,[2,3] this is a very easy recommendation for clinicians. It's simple advice, nonpharmacologic, and doesn't have side effects.
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Cite this: What Causes Parkinson Disease? - Medscape - Jul 02, 2012.