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Animal models that suffer from the same diseases as humans are perhaps our most valuable resources for studying those conditions. Whether researching cancer in mice, tuberculosis in guinea pigs, or osteoarthritis in horses, scientists use such animals as accelerated case studies. Animals develop diseases more quickly than humans do. They can also be tracked continuously throughout the course of a disease and (unwittingly) serve as test subjects for risky, experimental treatments.

But as useful as these models are, not every condition we hope to study occurs in animals.¹ Humans are unique, after all, with our disproportionately large brains, longer lifespans, consumption of processed foods, and artificial living spaces.

Parkinson’s is one of the diseases that many think could be unique to humans. Its causes are still unclear — genetics and environmental factors both seem to play a big role — but the disease generally has three features: chronicity, progression, and death of dopaminergic neurons, gradually leading to movement disorders. A “good” Parkinson’s model would need to capture these same features; once the disease process starts, it should not spontaneously halt without treatment (chronic), symptoms should worsen or expand over time (progressive), and it should exhibit the hallmark loss of dopaminergic neurons.

When lacking a natural animal model, researchers are often forced to rely on “inducing” conditions in animals where they would not normally arise. This is common in Alzheimer’s and AIDS research, where mice are genetically modified to express human genes associated with that disease. But as treatments tested on these induced animals fail to translate to humans in more than 92 percent of cases, researchers prefer working with “natural” models.

Parkinson’s researchers also induce animals to study the disease, often by injecting mice or monkeys with a neurotoxin called MPTP, which destroys dopaminergic neurons.² MPTP toxicity, though, doesn’t perfectly replicate the chronic, progressive nature of Parkinson’s; in some cases, symptoms plateau or partially reverse over time. Perhaps it is unsurprising, then, that after decades spent observing MPTP-treated animals (as well as the few unfortunate humans who accidentally self-administered the same neurotoxin), these induced-Parkinson’s experiments have not yielded any major breakthroughs.

While there are Parkinson’s treatments that can decrease some symptoms, none are capable of altering the course of the disease. Are Parkinson’s researchers doomed to rely upon these imperfect animal models forever?

Perhaps not. In 2020, researchers at the Kunming Primate Research Center in China reported finding a cynomolgus macaque with what they claimed was naturally occurring Parkinson’s. Cynomolgus macaques, small primates native to Southeast Asia, are already widely used in drug development research. If this study is accurate, it suggests there could be many more afflicted monkeys — and possibly other types of animals with Parkinson’s — out there. Maybe we just haven’t looked hard enough.

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Monkey Tremors

The researchers claim they found the sick monkey by doing random behavioral screenings and watching the animals for abnormal gaits or tremors. The Kunming Primate Research Center houses about 2,400 primates, from which the authors screened just 60 — half cynomolgus and half rhesus macaques. All the animals were healthy,³ had not been used in previous experiments, and were between 7 and 30 years old (young adult to elderly in macaque terms). The study also states the monkeys were screened without any bias toward age or caretaker suspicion. Out of those 60 monkeys, the researchers determined that one appeared to have Parkinson’s — a young adult just 10 years old.

I’m skeptical that the study’s authors really performed the random, unbiased screening that the paper suggests. It seems more likely that a caretaker already suspected that a monkey had Parkinson’s, prompting the team to test more animals to bolster their research. Even if my hunch is correct, though, it wouldn’t influence the details regarding this monkey’s symptoms.

After all, the monkey appeared to have Parkinson’s. In a video included in the study, the animal is visibly shaking, unsteady on its feet, and unable to grab the bars of its cage properly — classic symptoms in humans with advanced, untreated Parkinson’s disease. The monkey also responded to standard treatments: When given L-Dopa — a molecule that imperfectly compensates for the dopamine lost from dying neurons — its tremors subsided. The researchers also administered apomorphine, another Parkinson’s medication, and saw similar improvements.

After euthanizing the monkey, the team studied its brain and noted a severe loss of dopaminergic neurons — about 70 percent fewer than healthy, control monkeys. These neurons normally make and respond to dopamine, which, among other things, is responsible for coordinating movement in the body. Researchers also found about fivefold more alpha-synuclein aggregates in the monkey’s brain, implicated in forming the Lewy bodies linked to dementia in later-stage Parkinson’s.

And finally, the genetic analysis was strongly suggestive. The monkey carried four mutations in the LRRK2 gene, according to the study, which has been tied to Parkinson’s in humans and is known to cause Parkinson’s-like symptoms in mice. The researchers also ran follow-up experiments in the laboratory; cell lines carrying the same mutations as those found in the monkey had similar RNA expression patterns as cells taken from Parkinson’s patients.

Unfortunately, it’s still unclear whether these specific mutations in LRRK2 actually caused the monkey’s disease. The researchers did not sequence other monkeys in the colony to see if similar mutations were present in monkeys without Parkinson’s, so we don’t know for sure whether environmental or other genetic factors were to blame.⁴

Also, despite the nearly five years that have passed since this study was published, I’m not aware of any other reports showing Parkinson’s disease naturally occurring in a monkey or any other animal. Does this undermine the study’s findings?

Not necessarily. LRRK2-based Parkinson’s mutations occur in roughly 0.1 percent of humans, but they are often only partially penetrant. One common mutation in the LRRK2 gene — called the G2019S variant — has an estimated 25 percent penetrance in humans. In other words, not everyone who carries the mutation will develop Parkinson’s. If cynomolgus monkeys shared both this prevalence and penetrance, then, only about 1 in 1,000⁵ would carry a LRRK2 mutation and an even smaller fraction would actually develop the disease from such a mutation.⁶

In humans, untreated Parkinson’s causes a gradual breakdown in movement and, often, cognitive impairment. It takes about seven years from symptom onset until Parkinson’s patients begin falling regularly while walking. But monkeys live one-fifth as long, so symptom onset to death might take only six months or a year, due to the rapid progression of neurodegeneration.

Few research facilities care for thousands and thousands of monkeys, so it’d be easy to miss Parkinson’s cases. Even in larger centers, staff would not necessarily spot an unexpected disease, especially if the animals had short lifespans or their symptoms mimicked more common illnesses.

The Tulane Primate Research Center in Covington, Louisiana is one of the largest animal facilities in the United States. It houses about 6,000 monkeys. If LRRK2-related Parkinson’s occurs at a rate of 1 in 1,000 monkeys over a 20-year lifespan (a rough estimate), then the annual chance of any given monkey developing Parkinson’s is 1 in 20,000. In the Louisiana colony, we would therefore expect only 0.3 new cases per year, leading to a 26 percent probability of at least one new Parkinson’s case annually. Thus, any primate facility trying to replicate the Chinese team’s findings in a single year might well fail — one-in-four odds, while better than nothing, are certainly not guaranteed.

And even if a monkey did have Parkinson’s, it could become so impaired that it dies before detection. Or, depending on how old these monkeys are, they may be in a “prodromal” (presymptomatic) rather than in a symptomatic stage. Many other conditions — especially viral infections or age — can also cause similar symptoms to those observed in Parkinson’s. Researchers might simply see an adult animal that struggles to eat, is shunned by its fellow monkeys, and then passes away from “natural causes” — life as usual in a vivarium.

But perhaps there is a more efficient way to identify animals with Parkinson’s, or other neurodegenerative diseases, before they perish.

Upping the Search

Large vivariums like the one at Tulane already have the means to identify naturally occurring cases of the disease, simply by sequencing every animal for Parkinson’s-linked mutations — not only LRRK2, but also rarer mutations in SNCA or PRKN genes.

Of course, pinpointing which mutations are truly disease-associated in monkeys can be challenging. One option is simply to sequence every monkey, catalog all genetic variants, and then track which monkeys (if any) develop Parkinson’s-like symptoms. Researchers could then trace a monkey’s symptoms back to its genetic identity. And even if this plan were to fail entirely, and the monkeys didn’t develop Parkinson’s after all, creating such a genetic library would still be valuable for understanding how — or whether — monkey orthologs mirror their pathogenic counterparts in humans.

Animals suspected of having Parkinson’s could be immediately segregated out to form a new breeding colony. Those animals could also begin receiving treatments, such as L-Dopa, to test their effectiveness. Animals with advanced forms of Parkinson’s could be sacrificed and their clinical pathologies studied using microscopes and histology. Other animals could get follow-up behavioral screenings every 6 months or so.

This would not be prohibitively expensive and would be well worth the potential upsides of finding an animal model that leads to lucrative treatments. A single animal can be sequenced today for about $300 and behavioral screening performed (based on technician labor) for about $75. It costs about $50 to treat one animal for one month and about $500 to perform detailed pathology experiments on neural tissue.

The biggest outlay, by far, would be the initial cost of sequencing, which, for a 2,400-animal facility like the one in China, would run to almost $1 million. Fortunately, to establish a breeding colony, that sequencing would only need to occur once. Assuming that a facility located fewer than 10 primates with relevant mutations, the rest of the costs would be less than $10,000 per year.

The Tulane Primate Research facility recently received a $42-million, 5-year grant from the National Institutes of Health, or about $8 million a year. An initiative like this would therefore be about ⅛ of its annual budget initially, and a negligible amount after that.

If researchers independently confirmed Parkinson’s in other monkeys, the findings would also imply that a variety of other animals could develop the disease, too. Since LRRK2 mutations analogous to those found in humans can be induced in mice to produce Parkinson’s-like symptoms, it’s reasonable to assume that a small percentage of other species could inherit these variants.

The benefits of a natural, fully-developed model of Parkinson’s would be incalculable. Right now, we don’t know why Parkinson’s develops, how to identify it in its prodromal phases, or, crucially, how to prevent it. At our current rate of progress, we’re unlikely to make these research breakthroughs any time soon. As it stands, people only get diagnosed with Parkinson’s once it becomes symptomatic, at which point there’s already been a fair amount of neurological damage.

Similarly, our treatments for Parkinson’s have not progressed that far beyond the original discovery of L-Dopa to reduce tremors.⁷ There are attempts to develop disease-modifying treatments, like using stem cells to regrow neurons, but any therapies affecting the brain are necessarily complex and dangerous. The infirm, elderly patients who make up the majority of Parkinson’s cases would most likely resist entering such complicated or dangerous trials.

If, however, we could reliably isolate lab animals with a high probability of getting diagnosed with Parkinson’s before they’re born, we’d be able to investigate the development of the disease in many different ways, such as blood-based biomarkers, pathology, or brain scans. We’d also be able to explore what factors are protective against Parkinson’s (i.e. why some animals with certain mutations develop it and others don’t), carry out preventative studies, and perform the sort of intensive interventional studies that are unethical to do with elderly humans.

Assuming we do successfully identify animals with Parkinson’s, we will have necessarily found the best animal models for the study of the disease. And even if it turns out that only primates, like the cynomolgus monkeys, can develop Parkinson’s, we’ll still have a model in which the disease develops much more quickly and one that can be kept in a lab. These monkeys could prove just as important for Parkinson’s research as guinea pigs were for tuberculosis, presenting the missing piece that could potentially lead to a cure.

We just have to be more resolute in our search.

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Trevor Klee is a blogger and president of Highway Pharmaceuticals, a company making drugs for animals and humans. He’s looking for people who are interested in pursuing this search for naturally occurring Parkinson’s in animals. If you’re interested, please contact him at trevor[at]highwaypharm.com.

Cite: Trevor Klee. “A Search for Sick Animals.” Asimov Press (2025). DOI: https://doi.org/10.62211/47ur-65jg

Lead image by Ella Watkins-Dulaney.

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Footnotes

1. Only a handful of species menstruate, for example, which complicates studies of reproductive disorders. Down syndrome requires precisely 46 chromosomes, which only humans have.
2. There are other induced chemical models, too, including 6-OHDA and rotenone. All of them have the same issue of not causing a disease that is chronic or progressive, however.
3. It’s unclear how monkeys can be both healthy and suffering from Parkinson’s, but I’m guessing they mean they were otherwise healthy.
4. Humans who smoke cigarettes appear to have a reduced risk of Parkinson’s, for example, whereas those exposed to pesticides seem to have an increased risk. In short, as a person’s environment appears to play a role in triggering the disease, a similar influence might be presumed in monkeys.
5. It’s hard to say a more precise number than “1 in 1,000” without getting into the weeds on genetics, as mutation rates vary widely across organisms and different parts of the genome.
6. Overall, the lifetime risk of Parkinson’s in humans is often estimated to be around 1–2 percent, and about 90 percent of cases have no known genetic cause.
7. Levodopa works for a time, but motor fluctuations and dyskinesia do reappear. One large, prospective study, called STRIDE-PD, found that more than 50% of Parkinson’s patients “develop motor complications, fluctuations and/or dyskinesia, after 4 years of treatment with levodopa at an average dosage of 400 mg daily."

This article was originally published on February 5, 2025.