Shaping the Future of Parkinson’s Treatment: Dr. Greenamyre’s Contributions and Outlook
The American Parkinson Disease Association (APDA) is committed to furthering Parkinson’s disease (PD) research and proudly invests in the most promising clinicians and scientific projects focused on the discovery of the cause(s) and finding the cure(s) for PD. Our Centers for Advanced Research, along with a variety of funded grants and fellowships, are the backbone of our research program.
J. Timothy Greenamyre, MD, PhD, is the director of APDA’s Center for Advanced Research at the University of Pittsburgh, as well as a long-standing member of APDA’s Scientific Advisory Board. At the University of Pittsburgh, he serves as the Love Family Professor of Neurology and has led the Pittsburgh Institute of Neurodegenerative Diseases (PIND) for twenty years. PIND recently honored him with a Lifetime Achievement Award in recognition of his monumental contributions to PD treatment and research.
We had the opportunity to catch up with Dr. Greenamyre, and we’re eager to share his insights into the compelling research he has underway and why he remains optimistic about the future for people with PD.
A Conversation with Dr. J. Timothy Greenamyre
Q: You are a pioneer in studying the interaction between environmental and genetic causes of PD. What first drew you to this field of research?
A: It was a convergence of findings from around the world that drew me to the field, including:
- Epidemiological studies that found an association between pesticide exposure and increased risk of PD.
- Clinical observations that people exposed to MPTP – an organic compound that becomes toxic in the brain – developed acute, severe PD-like symptoms, suggesting that environmental toxicant exposures can cause PD.
- Laboratory findings that MPTP becomes toxic in the brain by interfering with an enzyme called complex I in the cell’s “power plants” (known as mitochondria), specifically in the brain cells that make dopamine, a key chemical involved in movement, which is deficient in people with PD. What’s more, it was found that the complex I enzyme was defective in people with PD, and the defect was not limited to nerve cells that die in PD – it was found throughout the brain and body.
- The discovery of the first genetic cause of PD: mutations in the alpha-synuclein gene. It was also found that alpha-synuclein protein clumps make up the Lewy bodies that are characteristic of PD, although the method through which alpha-synuclein clumps into Lewy bodies was unknown.
This was where things stood as I was completing my clinical training in neurology and starting my career. At the time, there was general skepticism about the relevance of the complex I defect. That is, how could a systemic defect in this enzyme (present throughout the brain and body) result in the highly selective degeneration of dopamine-producing brain cells that occurs in PD? And what did this have to do with alpha-synuclein?
To address the relevance of the complex I defect, I needed a way to cause a systemic complex I defect like that in PD (and unlike MPTP, which only inhibits complex I in dopamine neurons). For this purpose, I used a natural complex I inhibitor called rotenone, which has chemical properties that allow it to distribute throughout the brain and body. I had the idea that, if I could inhibit complex I systemically to an extent similar to PD, it might be possible to reproduce some aspect of PD. And in fact, when rats were treated with rotenone, it caused complex I inhibition uniformly throughout the brain and body, and, amazingly, it caused PD-like motor impairments, degeneration of the same dopamine neurons that die in PD, and abnormal clumping of alpha-synuclein into Lewy body-like structures!
What made this even more exciting was that the complex I inhibitor we used, rotenone, was also a commonly used pesticide. In this way, we managed to tie together, in one model, pesticide exposure, systemic complex I inhibition, abnormal clumping of alpha-synuclein, selective degeneration of dopamine neurons, and PD-like motor behaviors. Another aspect of this work was that it was our first demonstration of gene (alpha-synuclein)/environment (rotenone) interactions. It has subsequently been shown that exposure to rotenone is a bona fide risk factor for PD in humans, so our work has come full circle.
Q: What is your lab’s primary research focus right now, and what are the possible implications for people with PD?
A: Our focus is currently on the most common genetic cause of PD: Leucine Rich Repeat Kinase 2 (LRRK2, pronounced “LURK-TOO”). As always, we are focused on gene-environment interactions, and we’re still using rotenone. We have strong evidence that LRRK2 plays a key role in PD, even in people without LRRK2 mutations. Practically speaking, this means that drugs and other therapeutics that are being developed for those with LRRK2 mutations may also be effective for everyone with PD. Clinical trials to test this idea are underway, and it is my hope that this work will lead to the first unequivocal “disease modifying” (or “neuroprotective”) therapies for PD, which could slow, stop, or reverse the underlying progression of the disease, rather than just manage symptoms.
Q: What do you wish more people understood about the findings in this field of research? Are there any common misconceptions you’d like to clear up?
A: Two things come to mind. First, I want everyone to know that, for most people, the risk of developing PD is a combination of your genetic make-up and your history of environmental toxicant exposures. (However, for some people with PD, a single genetic mutation or extensive toxicant exposure may be identified as the most likely cause.) It should also be known that environmental toxicants that might cause PD include pesticides, solvents, and certain types of air pollution. Microplastics may also play a role, since they travel into the brain easily. And it is worth emphasizing that a great deal of time can elapse between key exposures and the development of PD.
And secondly, as many people with PD choose to take nutritional supplements, I want to point out that, unlike FDA-approved prescription drugs, supplements are not regulated. They may contain chemicals, pharmaceuticals, and neurotoxic heavy metals. In extreme cases, they may worsen PD symptoms. When possible, I suggest taking supplements with USP certification. USP is a global organization that sets public quality standards for medicines, dietary supplements, and foods. Also, “natural” does not mean “safe.” Some of the most toxic chemicals, such as cyanide, are natural. And rotenone, which we use to cause “PD” in rats, is also natural – it comes from leaves and roots of certain plants.
Q: As a movement disorders neurologist, you also treat PD patients. How do your interactions with patients influence your research pursuits?
A: To the extent possible, we try to take issues from the clinic and attack them in the lab (using rats). As an example, we have been able to reproduce in rotenone-treated rats the constipation that often bothers people with PD. This may provide a way to test new therapeutic approaches for constipation.
We have also discovered new pathological features in the brains of rotenone-treated rats that were subsequently shown to occur in brains of people with PD. In other words, the rotenone “model” predicted what we would find in brains of humans with PD. In some cases, we have successfully used new drugs to prevent or reverse these abnormalities in rats – and we hope to do the same in people with PD.
I would be remiss to not mention brain donation here – a difficult but important topic that sometimes comes up during visits to the neurologist. It is essential that we have a brain bank that includes both people with and without PD. Although it is equally important, it is generally more difficult to collect brains from those without PD. But only by studying PD brains and comparing them to brains unaffected by the disease can we truly understand what’s happening in PD. We need your brains!
Q: Many in the PD community are eager for faster progress. What gives you hope that we’re making meaningful progress toward a cure?
A: I think we are finally beginning to understand the basic cellular mechanisms that lead to the pattern of neurodegeneration that we call PD. With this improved understanding, we have been able to design new therapeutics that are at last getting to the heart of the matter. I am optimistic that within a few years we will have the first of a series of “disease modifying” (or “neuroprotective”) therapies.
Q: After decades studying PD, you were diagnosed with the disease yourself in 2021. How has that affected your outlook on the research?
A: My diagnosis has not really altered my outlook on PD research. Of course, I eagerly await a breakthrough therapy, but that longstanding desire has not been changed by my own diagnosis.
Q: What is one piece of advice you would give to someone who has been recently diagnosed with PD?
A: I’ll offer two: First, establish care with a trained movement disorders specialist! As a movement disorders neurologist myself, I frequently see misdiagnoses and inappropriate, ineffective management of symptoms. Second, as you educate yourself about PD, stick to reputable sources of information, such as APDA and other trusted PD organizations. Steer clear of personal blogs, testimonials, and so-called miracle cures – unfortunately, there’s no such thing… yet!
Q: You are a long-standing member of APDA’s Scientific Advisory Board and serve as director of APDA’s Center for Advanced Research at the University of Pittsburgh. What keeps you so committed to APDA?
A: First and foremost, it’s the people – the APDA staff and their scientific advisors, starting with Dr. Fred Wooten 30 years ago. Second, of course, is APDA’s mission to “provide the support, education, research, and community that helps everyone impacted by PD live life to the fullest.” And I’ll always have a sentimental connection to APDA – they gave me one of my very first research grants when I was just starting out.
Q: If you had never become a movement disorders neurologist and PD researcher, what would you be doing instead?
A: That’s really hard to say. From the outside, my career path might seem well planned and logical, but it was actually a series of happy “accidents” – meeting the right people at the right time, each of whom had a profound impact on me and influenced my decisions. In reality, nothing was planned. So, because I didn’t have a “Plan A,” I didn’t really have a “Plan B”! Maybe I would have been a photographer.
Tips & Takeaways
- APDA’s Centers for Advanced Research, along with a variety of funded grants and fellowships, are the backbone of our research program.
- Dr. J. Timothy Greenamyre – director of APDA’s Center for Advanced Research at the University of Pittsburgh and long-standing member of APDA’s Scientific Advisory Board – is a pioneer in studying the interaction between environmental and genetic causes of PD. His research is currently focused on LRRK2, the most common genetic cause of PD, and related gene-environment interactions. It is his hope that this work will lead to the first unequivocal disease modifying therapies for PD.
- For most people, the risk of developing PD is a combination of genetic make-up and history of environmental toxicant exposures. Environmental toxicants that might cause PD include pesticides, solvents, and certain types of air pollution.
- Recently diagnosed? Dr. Greenamyre’s top tips: establish care with a trained movement disorders specialist and stick to reputable sources of information. You can get started here.
- You can support APDA’s mission, including our national research program, by making a donation here. Thank you.