Dan Keller 0:08
Welcome to this episode of Substantial Matters: Life and Science of Parkinson’s. I’m your host, Dan Keller. At the Parkinson’s Foundation, we want all people with Parkinson’s and their families to get the care and support they need. Better care starts with better research and leads to better lives. In this podcast series, we highlight the fruits of that research—the treatments and techniques that can help you live a better life now, as well as research that can bring a better tomorrow.
The journey to new therapies for Parkinson’s and other diseases depends on clinical trials involving people with the disease to prove the efficacy and safety of any new treatment. The road to clinical trials starts with preclinical studies—laboratory experiments involving animals, cells, or isolated biological compounds or systems as models.
Richard Smeyne is a professor of neuroscience at Thomas Jefferson University in Philadelphia focusing on Parkinson’s disease. His laboratory uses preclinical models to study mechanisms of neurodegeneration and neuroprotection, talking about preclinical models of Parkinson’s disease.
What does preclinical mean first of all, and how does this add to useful knowledge that may eventually help people with Parkinson’s?
Richard Smeyne 1:38
When I think of preclinical models, I generally think of studies that do not involve humans. Often they’re the early studies using animals, or we can use cell lines, or we can use single-cell organisms such as yeast to study a variety of biochemical mechanisms that we know or think underlie development of Parkinson’s disease.
And these are very useful because they give us the clues on the pathways that are affected, the biochemistry, sometimes even anatomical circuitry underlying the disease. And it’s a way that we can use them to intervene for potential therapies down the road that can then be used in human trials.
Dan Keller 2:20
Do they generally pan out? What’s your batting average there?
Richard Smeyne 2:24
It’s interesting when you ask that question. Many of the therapies that we know work in animal models or in cell lines in terms of rescuing do not work in humans, and that’s always a potential problem.
And one thing we have to recognize in our preclinical models, especially related to Parkinson’s disease, is that Parkinson’s disease is a uniquely human disorder. In any of the models that we’ve made to examine Parkinson’s disease, they do not recapitulate what we see in the disease spectrum seen in people.
So we have to choose. When we’re doing animal models, we can study the loss of cells, or we can study biochemistry or processes, but not the whole disease.
Dan Keller 3:07
Is Parkinson’s disease even one disease in people? You have various genetic causes, interactions of genes. So when you study it in a preclinical model, do you have to pick what kind of underlying deficit there is?
Richard Smeyne 3:23
We do. But your initial question is actually critical to our understanding of Parkinson’s disease, and we don’t quite have a handle on that now.
Many years ago, we thought of Parkinson’s disease as a single entity, and it was sort of all-encompassing. With the advent of modern genetics and the identification of many different genes that lead to Parkinson’s disease, we now have to ask the question: is Parkinson’s a better term than Parkinson’s disease? Because many different ways can eventually give you similar symptoms.
And this is a critical question when we’re thinking about therapy. Do we have a single treatment that would be good for all forms of Parkinson’s, or do we have to identify these subgroups of people because they’ll be treated differently?
I often think about Parkinson’s disease using a cancer analogy. 15–20 years ago, you would tell someone you had cancer. Nowadays, if you say “I have cancer,” it becomes virtually meaningless—it is what type of cancer, what mutation underlies it, because individualized therapies are coming now.
That’s likely the future in many neurological disorders, including Parkinson’s disease.
Dan Keller 4:36
I suppose like in cancer, the more defects you find, the more each case becomes a rare disease. You’ve got A, B, C, and Z, and different types of cancers or reasons leading to Parkinson’s.
Richard Smeyne 4:53
Absolutely. And the more we know about genetics, the less we know about the disease in a way. Once we get a better understanding of underlying genetics, we may have more personalized medicine available to everybody.
As you said, you may have a defect or mutation or epigenetic alteration controlling gene expression. We can see this in screening as it becomes cheaper and technology improves.
Then we can personalize treatment. This is where preclinical studies are at the forefront, because depending on the process interfered with, you may use one class of drugs, and if another process is involved, we may use a different approach, hopefully still achieving the same positive outcome.
Dan Keller 5:49
Can you give me one or two examples of preclinical studies that have progressed and led to phase 1, 2, or 3 studies or even an actual drug?
Richard Smeyne 6:00
The ones that are furthest along now are studies examining alpha-synuclein. Alpha-synuclein is the protein that is misaggregated—it forms clumps within cells—and is thought to underlie much of the disorder.
We know this process normally involves non-aggregated alpha-synuclein, but with mutations or other defects it clumps. So we have studies preclinically using different drugs that stop aggregation, and we are moving into therapies using either passive or active antibodies that interfere with transmission of this altered synuclein, aiming to reduce misfolded protein.
Those are now being transferred from the laboratory and pharmaceutical companies into human trials.
There are also other studies, for example from Hopkins, looking at a molecule called LAG3, which interferes with aggregation. Other studies from Georgetown are looking at drugs affecting the c-Abl gene, originally an oncogene but now known to be involved in the proteasome system.
A drug called nilotinib, a small molecule, interferes with c-Abl signaling and may help disaggregate synuclein or prevent aggregation, lowering synucleinopathy.
Dan Keller 7:42
What you’ve described is often termed bench to bedside. What about going the other way—bedside to bench? What you learn at the bedside?
Richard Smeyne 7:55
Absolutely. When I think of bedside to bench, I don’t think so much about drug therapy alone, but about alternative therapies—things people do that we know can interfere with disease progression.
Exercise is a perfect example. Epidemiology shows people who exercise tend to have slower progression or lower risk of Parkinson’s disease.
My lab and others have taken that observation and studied it in animal models where we can control exercise and examine biochemical changes in the brain. From that, we’ve identified pathways that change with exercise that can be targeted.
Another example is MPTP in heroin users who accidentally developed Parkinsonian symptoms. This led to discovery of MPTP, which helped identify mitochondrial dysfunction and bioenergetic failure in substantia nigra dopaminergic neurons.
From that, we’ve identified genes and biochemical processes that can now be targeted in therapies.
Dan Keller 10:10
As Yogi Berra said, “You can observe a lot just by looking.” It sounds like serendipity plays a role.
Richard Smeyne 10:27
Absolutely. This is a secret of science. Look for things that are out of the ordinary. The MPTP story required detective work, and many people contributed.
It happened in different places, including Baltimore with Barry Kidston and later work by Bill Langston, who is often credited for advancing the field.
Yes—keeping your eyes open for unexpected findings is critical. Many discoveries come from outside Parkinson’s research and are incorporated by scientists who read broadly across fields.
Dan Keller 11:37
Do you think there’s even more need for reading outside your field?
Richard Smeyne 11:48
Absolutely. Both clinicians and basic scientists need to read outside their fields. Parkinson’s disease is not just a motor disorder—it includes gut, immune, and cognitive systems.
It is difficult for one person to master everything. The field is now highly interdisciplinary, involving immunologists, molecular biologists, anatomists, pharmacologists, and physiologists working together.
We can no longer be siloed. We need collaboration across disciplines.
Dan Keller 13:24
What have we missed that’s interesting?
Richard Smeyne 13:24
One important point is how much we can learn from different organisms. Yeast, C. elegans, flies, rodents, and non-human primates all contribute important insights.
These models are not meant to cure animals but to improve understanding of disease processes in humans.
Dan Keller 14:15
Good. Thanks.
Dan Keller 14:24
To learn about research and drug development, visit parkinson.org and search “research” or “drug development.” You can also call our toll-free helpline at 1-800-4PD-INFO.
If you have questions or feedback, visit parkinson.org/feedback.
Our mission is to help every person diagnosed with Parkinson’s live the best possible life today. New episodes are released every other week.
For more information, visit parkinson.org or call 1-800-473-4636.
Thank you for listening.
