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.[1] 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.
Medscape: You presented some interesting exposure data at yesterday's session.[4] What specific environmental exposures have been linked to PD?
Dr. Tanner: The chemical MPTP -- one of the most extensively studied compounds known to induce parkinsonism in humans -- is a very rare cause of parkinsonism. In the laboratory, MPTP causes oxidative stress and impairs mitochondrial function. Paraquat, a commonly used herbicide, is similar in structure to MPTP. In the laboratory, paraquat also causes oxidative stress and a Parkinson-like condition in animal models. This prompted several people to look at whether or not pesticide exposure and agricultural work might be associated with PD risk.
Big exposure categories, such as pesticide use, began to be identified, but getting details on specific chemicals was difficult because it required getting the life histories on the subjects. This was a bit of an impasse, because there are many different types of pesticides with very different biological effects. It seemed unlikely that all pesticides would be associated with PD.
That's why we started taking detailed occupational histories to collect pesticide exposures. And we did find paraquat to be associated with risk for PD in several different populations. One was an occupational case/control study where there were relatively few exposed people, but those who were exposed had a 2.5 times greater risk. Then we went to the farming population, because we knew they had to keep good records on what chemicals they've used. Again, we found paraquat to be associated with PD. So this association is becoming fairly convincing.[5]
The other thing in our recent paper was the finding of an increased risk for PD associated with rotenone. Rotenone has been used in research to block mitochondrial complex 1 in the laboratory for years. It's a naturally occurring compound in numerous plants, and native people had recognized it to be poisonous; they would grind up rotenone-containing plants and put them in the water to stun fish. It's been used in a wide range of pesticide products over the years -- including household products, such as flea powders; insecticides for houseplants or gardens; and home pest removal, as well as commercial products -- so it's hard to answer the question, "Were you exposed to rotenone?" But by studying farmers and their spouses, who actually had records on whether or not and when they used it, we were able to find a specific association with PD.
A third compound that I didn't talk about yesterday is 2,4-D (2,4-dichlorophenoxyacetic acid), which is also an herbicide and is a component in Agent Orange. As we were reporting an association between occupational exposure to 2,4-D and PD, the Veterans Administration reported that veterans exposed to Agent Orange were entitled to disability benefits for PD. Their determination was based on other information, not on our work, and they didn't make specific reference to 2,4-D exposure of course, but it's interesting that we came to the same conclusion through studying 2 different types of exposure to the same chemical.
I should say that our other study did not show an association with 2,4-D despite some of the farmers having used the agent, so these findings still need replication. Also, it is essential for basic scientists to study the effects of these chemicals associated with PD in humans in the laboratory, because there's no incentive for the pesticide manufacturing industry to identify new adverse health effects of pesticides. Their interest is in figuring out whether or not a compound kills the pest. And unless they're told to, they're probably not going to be doing studies on adverse health effects. So, we need scientists to be looking at these chemicals in the laboratory.