“So let me get this straight. You make mice get Parkinson’s disease, then you try to figure out how to make them better, right?” That was my 10 year-old son summarizing my research career, one in which I’ve focused on modeling Parkinson’s disease and related neurodegenerative disorders in animals as well as in cells grown in the lab. “Seems like a reasonable way to go about it” he added. It’s always nice to be affirmed by one of your fiercest critics.

Why Model PD?

Like for many chronic diseases, our understanding of the mechanisms that underlie PD still contains significant gaps. What causes it? Why are some people affected but not others? Can we slow down or even reverse the disease?

Imagine for a moment that researchers were able to recapitulate all the things that occur in human PD in an animal. This ability would greatly enhance our efforts to develop new treatments for this disease by providing a tool for testing their effectiveness, and perhaps identify the optimal stage of disease during which to apply these treatments. Ineffective or unsafe treatments would be identified before they reach patients. It might also reveal previously unrecognized aspects of disease, for example events in early stages, that are hard to detect in human subjects.   

Can PD Be Modeled In Animals?

Of course, to effectively model any disease with such precision requires that a near-perfect comprehension of its causes, something which we do have at this moment. Nevertheless, the past few decades have seen a tremendous amount of clinical, genetic, and epidemiological data gathered from individuals with PD and other neurodegenerative diseases. While these observations do not give us a full explanation of the disease, they have allowed us to form hypotheses (i.e., informed guesses) as to why certain processes or symptoms occur, which we can then try to emulate in animals to study in further detail. These hypotheses have led to the development of three main categories of PD animal models:

1) Toxin models – where animals are exposed to certain chemicals that have been associated with an increased risk of PD in humans, for example MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) and certain pesticides which damage parts of the brain that are vulnerable in PD.

2) Genetic models – animals that have been engineered to contain genetic abnormalities (e.g., a gene mutation or absence of a gene) that is observed in some cases of human PD. For example, mutations in the gene for alpha-synuclein (a protein found in Lewy bodies) or glucocerebrosidase (an enzyme that helps cells to clear unwanted proteins).  

3) Pathogen models – administration of a rogue protein, bacteria or virus that induces PD or PD-like symptoms in animals. For example, alpha-synuclein extracted from PD patients can coax the natural form of this protein in neurons into forming Lewy body-like pathology in the brains of animals that they are inoculated into.    

As the late British statistician George Box noted, “All models are wrong, although some are useful.” Although no individual model of PD replicates all the features seen in humans, they have provided some important insights by validating many of the original hypotheses that led to their creation. Thus, we now have experimental information about how different individual processes might result in a particular feature of PD. Indeed, understanding how these various events coincide and influence each is a key focus of PD research. Even when models fail to behave as predicted, important lessons can still be gleaned as this could indicate that the underlying hypothesis was incorrect or incomplete, which can be helpful when prioritizing scarce resources.

Why Animals?

PD a multisystem condition that affects a myriad of tissues in the body and it should come as little surprise that the complexity of PD mirrors the biological complexity of humans. This means that in order to accurately model PD, the model organism needs to be sufficiently complex. Mice remain the most popular choice due to genetic tools already available, although other species ranging from worms, fish, rodents, and non-human primates have also been used. And while experimentation with animals (especially in species closest to humans) comes with physical and social costs, it is also the most likely to provide insights that can be translated to human health. Scientists, including myself, are continuously trying to mitigate this through practicing what is known as the 3R’s: Replacement (seeking alternatives where possible), Reduction (making sure that only the necessary number of animals are used), and Refinement (updating methods as to cause minimal discomfort to animals). A fourth “R” is Respect for these animals, knowing that they have contributed to improving our health.

Is It Worthwhile?

Even though we still lack a perfect model of PD, and may never arrive at recapitulating the full devastating complexity of the human condition, the imperfect animal models available have already greatly enriched our understanding of the disease. They have done so by confirming or challenging hypotheses. They are also playing an important role testing new treatments currently in development and will likely help inspire the next generation of therapies to follow. For now, there is definitely still room for models.  

Kelvin C Luk, PhD MTR is currently Research Associate Professor of Pathology and Laboratory Medicine at the University of Pennsylvania and member of the Penn Center for Neurodegenerative Disease Research. Dr. Luk will be speaking about this topic as part of the WPC Research Spotlight series on Tuesday, July 12, 2022.

Ideas and opinions expressed in this post reflect that of the author solely. They do not reflect the opinions or positions of the World Parkinson Coalition®