Nearly one million Americans live with Parkinson’s disease (PD). As the disease progresses, people who have PD are likely to lose motor functions and the ability to live an independent life. Much of this is attributable to the drug treatment for PD that leads to abnormal, involuntary movements known as dyskinesias. Scientists at Yerkes National Primate Research Center have been probing the origin of these abnormal responses to treatment and have successfully tested a tactic for controlling them.

Dyskinesias are believed to be caused by fluctuations in dopamine, the neurotransmitter whose production is lost in the brains of those with Parkinson’s. The standard drug levodopa restores dopamine, but sometimes, in the process of achieving symptom relief, dopamine levels become too high, and responses are unstable.

Researchers led by Stella Papa, a Yerkes researcher and associate professor of neurology at Emory University School of Medicine, showed striatal projection neurons (SPN), which become hyperactive when nearby dopamine-producing neurons degenerate, could be controlled by certain drugs, reducing the rate of unstable responses to dopamine that cause dyskinesias.

“Our focus was to prove SPN hyperactivity plays an important role and that glutamate signals are a major contributor,” says Papa. “Knowing this mechanism may serve to develop different therapeutic strategies: pharmacological treatments or gene therapies.”

Yerkes researchers tested whether the drug LY235959 (an NMDA receptor antagonist) or NBQX (an AMPA receptor antagonist) could control SPN hyperactivity and dyskinesia symptoms in Parkinson’s model monkeys. The nonhuman primate model of Parkinson’s uses the neurotoxin MPTP, which destroys dopamine-producing neurons. Both drugs interfere with signals by the neurotransmitter glutamate. In the presence of levodopa, the drugs had calming effects. After lowering the SPN firing frequency by 50 percent, the response to dopamine stabilizes and abnormal movements are markedly diminished.

The particular drugs used are not ideal for human application, but they do reveal mechanisms behind dyskinesias. Researchers say these insights will be valuable to advance their research and, ultimately, develop new treatments with improved effectiveness for people who have PD.

What doesn’t kill you might just save your life.

At least, that’s the new thinking on how to combat SIV, a variant of HIV. This comes after researchers at the Yerkes National Primate Research Center sequenced the genome of the sooty mangabey – a nonhuman primate that can coexist with SIV – and discovered how an immune system deficiency actually stops SIV from turning into AIDS.

“We found two big differences in proteins of the immune system in the sooty mangabey genome, which we hope will help us better understand why sooty mangabeys avoid AIDS despite SIV infection,” said David Palesch, a Yerkes postdoctoral fellow and co-author of the study documenting the discovery.

These differences aren’t some biological defense system or super-simian invulnerability. Technically, they’re handicaps. Instead of a more robust immune system, the sooty mangabey is playing a man down in the fight against SIV and winning.

So what are these immune deficiencies? A missing piece in the the ICAM2 gene stops the corresponding protein from functioning – a genetic anomaly unique to the mangabey species.

Similarly, the TLR4 protein – a molecule that senses bacteria and triggers an immune defense against it – has limited functioning because of a genetic alteration.

“This finding is intriguing because damage to intestinal barriers and bacterial release contributes to chronic immune activation, which is associated with AIDS progression in HIV-infected humans and SIV-infected non-natural hosts,” said Guido Silvestri, chief of Microbiology and Immunology at the Yerkes Research Center.

Inspired by these findings, the Yerkes team is already planning its next study where the ICAM2 and TLR4 proteins will be manipulated in a living nonhuman primate host to determine how those genetic anomalies halt SIV’s progression.

“It’s a really exciting time in AIDS research,” said Dr. Steve Bosinger, assistant professor of Pathology and Laboratory Medicine and director of Yerkes’ Genomics Core. “We’ve seen that an HIV cure is possible.” Now, that’s something to be excited about.

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Photo credit: Yerkes National Primate Research Center

Top 10 Research Accomplishments at the NPRCs

The National Primate Research Centers (NPRCs) have played a crucial role in some of the most important medical breakthroughs of the past 50 years. NPRC research with nonhuman primates (NHPs) is highly regulated, provides unique insights not available with other models and often precedes clinical trials in humans. This list highlights 10 of the most significant, recent NHP research breakthroughs that are helping people across generations and the world live longer, healthier lives.

1. COVID-19 – The emergence of SARS-CoV-2 in 2019 was one of the greatest public health crises in American history, and NPRC researchers were crucial in the effort to address it. Results from NHP studies on transmission routes, pathogenicity and genetics of the virus, in addition to decades of research on other mRNA viruses, such as HIV, informed the design of human clinical trials and the safe and effective vaccines we have today. Furthermore, the two lead vaccines that have been given to tens of millions of U.S. nationals were both tested in nonhuman primates for safety, immunogenicity and efficacy, including one (Pfizer) at an NPRC (the Southwest NPRC). Several next generation vaccine candidates and therapeutics are currently being pre-clinically tested at different NPRCs.
2. HIV/AIDS – The emergence of HIV/AIDS in the early 1980s was one of the greatest public health crises in American history, and NPRC researchers were crucial in the effort to address it. Results from NHP studies on the ability of pre-exposure dosing of antiretroviral medicines to prevent infection with SIV or SHIV (the primate versions of HIV) informed the design of subsequent human clinical trials, which provided clear evidence that such pre-exposure dosing was effective in preventing infection.
3. Emerging Infectious Diseases – One of the most potent viruses to infect humans, Ebola is intensely studied by infectious disease researchers who work with NHP models to develop preventive vaccines and novel therapies. The disease course in macaques and marmosets is very similar to that in humans, and new vaccines and therapies have been tested in these animals. When Zika was identified in Brazil in 2015 and associated with severe birth defects, the infectious disease expertise of NPRC researchers was at the forefront of the scientific community’s response and early understanding of the disease’s pathology. Researchers are also working to 1) identify antiviral drugs that are effective against Zika in lab cultures and then test these drugs in NHPs; and 2) determine if and how Zika infection in pregnant animals results in defects of the fetal central nervous system.
4. Tuberculosis – TB kills approximately 2 million human beings each year. NPRC researchers have developed robust NHP models of the various presentations of the human TB syndrome, including those that permit the evaluation of the pathological granuloma, TB latency, TB/HIV co-infection and novel vaccine and therapeutic candidates, some of which are advancing to human trials.
5. Parkinson’s disease – Parkinson’s disease is a progressive neurodegenerative disorder that produces motor symptoms, such as tremor, walking difficulty and muscle stiffness, as well as many non-motor problems. NHP research led to an innovative surgical procedure called deep brain stimulation (DBS), which uses an implanted, battery-operated device to deliver electrical stimulation to specific brain areas that control movement. This blocks the abnormal nerve signals that cause the symptoms of Parkinson’s disease. NHP research also contributed to the development of autologous stem cells as a potential therapy for Parkinson’s and other neurodegenerative diseases. In 2007, researchers transformed skin cells from humans and monkeys into induced pluripotent stem (iPS) cells, and subsequently transformed the monkey iPS cells into dopamine neurons. Because transplanted neurons are able to differentiate into multiple different neural cell types and provide long-term increases in dopamine-producing neurons, such cells can be used to partially restore motor function in people who have Parkinson’s disease.
6. Brain-machine interfaces – This therapy combines neural recordings, computer representations of movement and robotics to allow monkeys and humans to manipulate their environments without the use of their arms. This research, which is dependent on NHPs, holds great promise for people who are paralyzed or who have suffered brain damage from stroke. Researchers have developed a brain-machine interface that enables monkeys to control robot arms with brain activity coded through a computer.
7. Huntington’s disease – Although the genetic defect responsible for this neurodegenerative disease is well known, the specific mechanisms by which the mutation induces the condition are not as well understood. NPRC researchers have developed a transgenic NHP model of Huntington’s disease by introducing a portion of the mutant human gene responsible for Huntington’s into fertilized macaque eggs. The result is transgenic animals that reproduce many of the key features of Huntington’s disease.
8. Stem cell research – This pioneering discovery, which NPRC scientists advanced from rodents to NHPs and then into humans in the 1990s, is already in early human clinical trials for macular degeneration, spinal cord injury, heart disease, ALS and more. There are approx. 30 clinical trials around the world involving embryonic stem cells and their derivatives. At least 40 trials involve the use of induced pluripotent stem cells. Pluripotent stem cell research has ushered in a new era of science and medicine that is dramatically expanding our options for pursuing cures and treatments.
9. Transplantation – NPRC researchers have developed a novel approach to suppressing immune responses to kidney transplants. The technique involves creating a fusion protein of a molecule that is involved in the stimulation of T cells, which sometimes reject transplanted tissue. This research paved the way for successful human clinical trials and FDA approval of belatacept, the first new transplant drug since 1999.
10. Mitochondrial disease – No treatment or preventive measures exist for this group of devastating human disorders, which present shortly after birth and can affect multiple organ systems to cause diabetes, deafness, blindness, dementia or epilepsy. Mitochondrial replacement therapy, or correcting dysfunctional mitochondria in the egg of a woman who previously delivered a child with mitochondrial disease, offers her the chance to have a typically developing child. NPRC researchers were the first to establish this process in NHPs by demonstrating the feasibility of replacing mitochondrial DNA in an egg with donor mitochondria from another egg, followed by in vitro fertilization and the development of typically developing offspring.

Updated February 2022

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Photo credit: Wisconsin National Primate Research Center

Understanding the genetic code is one thing. Altering it is something different altogether. Researchers at the Washington National Primate Research Center (WaNPRC) have discovered a technique for inserting a specific gene into the brain’s membrane, which could modify how the brain works, alter behavior, and potentially correct neurological disorders.

Researchers think that this approach, which involves genetically altering a select number of cells, might lead to treatments for neurological conditions such as epilepsy. “The brain is made up of a mix of many cell types performing different functions. One of the big challenges for neuroscience is finding ways to study the function of specific cell types selectively without affecting the function of other cell types nearby,” said lead researcher and associate professor of physiology and biophysics Gregory Horwitz. “Our study shows it is possible to selectively target a specific cell type in an adult brain using this technique and affect behavior nearly instantly.”

The research team inserted a gene into cells in the cerebellum, the parts of the brain controlling motor movements. Those cells, Purkinje cells, are some of the largest in the brain and connect with hundreds of other cellular structures.

The inserted gene, channelrhodopsin-2, creates a light-sensitive protein that inserts itself into the brain cell’s membrane. When exposed to light, the protein allows ions – tiny charged particles – to pass through the membrane.

By attaching the gene to a modified virus and painlessly injecting it into a small area of the cerebellum of rhesus macaque monkeys, the channelrhodopsin-2 was taken up exclusively by the targeted Purkinje cells. The researchers then showed that when they exposed the treated cells to light, they could affect motor control.

“This ‘transgenic’ approach has proved invaluable in the study of the brain,” Horwitz said. “But if we are someday going to use it to treat disease, we need to find a way to introduce the gene later in life, when most neurological disorders appear.” With this discovery, the researchers are one step closer to understanding the elegant system that is the brain.

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Photo credit: Kathy West for the California National Primate Research Center

‘Hippies’ are not all human; nonhuman primates have their own flower children. The muriqui monkey boasts famously low rates of aggression, spending much of its time hugging and socializing, and displays no hierarchy among males and females. Yet, through the work of a Brazilian-American research group led by Karen Strier, professor of Anthropology at the University of Wisconsin-Madison, the muriquis have emerged as a charismatic animal in need of help as habitat delines and populations dwindle.

In the effort to preserve the 2,300 muriquis in the wild, the research group asked an all-important question – What data do we need?

This question is especially important for studying multiple populations with differing habitat requirements, like northern and southern muriquis. Previous studies failed to maintain consistent methods, which produced results that were not comparable, so this team’s efforts are groundbreaking. “We think this may be one of the most comprehensive efforts to analyze the data monitoring needs for ensuring the survival of an endangered animal,” says Strier.

The study identifies genetic uniqueness and geographic importance as two key measurements that indicate whether a population can be used to enhance genetic diversity. Sex ratio and the proportion of females carrying babies allow scientists to understand population change. Methods should address feasibility, since many species inhabit locations impossible to reach, and be wary of fringe sites, as outlier populations are especially sensitive to climate changes.

Scientists are already applying this methodology to the northern and southern muriqui populations. The team is hopeful these methods can be used to study and save other endangered species.

The peaceful primates’ luck is looking up, as new muriqui reserves and abandoned farms make for hospitable environments to call home. “Seeing the resilience of nature makes me more determined than ever,” explains Strier. “We can’t reverse the past assaults to the planet, but we can do everything we can to stop them and give the animals and plants a chance to come back.”

Reviewed August 2019

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Photo credit: Wisconsin National Primate Research Center

While the public’s nervous obsession with Zika may be over, medical researchers still have questions. Can the virus survive in a nonhuman host? Can the blood of that nonhuman host infect others? For researchers at the National Primate Research Centers, it’s questions like these that drive their curiosity and compel them to find answers.

Scientists at the Wisconsin National Primate Research Center wanted to know if a mosquito bite can turn a nonhuman mammal into a virus carrier. To investigate this, they let Zika-carrying mosquitoes infect rhesus macaques. They then compared those monkeys and their symptoms to macaques that the researchers had injected with Zika.

The differences were small but significant. “It’s a difference of a couple days to what we call peak viremia,” says Dawn Dudley, a UW-Madison pathologist. Viremia is the medical term for when the virus enters the bloodstream. At that point, it can migrate from the spot of initial contact to other regions of the body where it may lie dormant, waiting to be passed on to someone or something else.

It’s unclear why the virus moves slower when delivered through a mosquito bite. “The biology of the disease probably depends a lot on how the mosquitoes transmit that disease – mechanically how they do it, and biologically what comes along with the virus when the mosquito bites,” says Tom Friedrich, a UW-Madison professor of pathobiological sciences.

The virus was also less likely to affect the central nervous system tissues of mosquito-bitten macaques.

Despite these differences, the virus never became strong enough to infect mosquitoes who fed on the macaques. “But that doesn’t mean other nonhuman primates couldn’t do that,” says Dudley. And with more questions, there’s always more research.

Reviewed August 2019

Feel that familiar tickle in your nose? You may be coming down with the common cold – a virus that has been afflicting humans for thousands of years.

One of the most ubiquitous illnesses, human rhinovirus (HRV) is responsible for more than 50% of cold-like illnesses and billions of dollars annually in medical visits and missed days of work. Yet, despite its prevalence and a nearly 60-year search, there is still no cure for the common cold.

But while most humans recover from the common cold in about seven days, a recent discovery of rhinovirus in chimpanzees resulted in a nearly 10% fatality rate. This is the first time scientists have seen rhinovirus cross the species barrier.

“It was completely unknown that rhinovirus could infect anything other than humans.” said Tony Goldberg, a professor in the University of Wisconsin-Madison’s School of Veterinary Medicine. “It was surprising to find it in chimpanzees, and it was equally surprising that it could kill healthy chimpanzees outright.”

The outbreak occurred in a chimpanzee community in Kibale National Park, Uganda. Of the 56 animals, five chimps between the ages of two and 57 died. A local veterinarian obtained a fecal sample from a deceased chimpanzee, allowing UW scientists to discover that the virus originated from a human cold host.

“We expected to see changes all over the genome,” said Ann Palmenberg, a UW-Madison professor of biochemistry. “But it is not a chimp-adapted virus.”

This discovery means that chimps are genetically predisposed to rhinovirus C, a particularly severe form of the common cold. This virus primarily affects young children with susceptible receptors, or “locks” that allows viruses to enter and infect cells.

“The virus found in Betty (a two-year old chimp) was one that looked like it came from a human, and the level of virus in the lung was comparable to what we see in children,” said James Gern, a Professor of Allergy and Immunology in the UW School of Medicine and Public Health. “There’s a species-wide susceptibility of chimps to this virus,” added Goldberg.

This discovery could have a major impact on scientist and zoologists alike. Goldberg suspects that rhinovirus C may have been overlooked for decades as a cause of chimpanzee death. Now, scientists are more motivated than ever to find a cure to the common cold — both for humans and their counterparts in the wild.

Reviewed August 2019

What causes infertility? The brain, of course.

With the discovery in 2013 that the ovaries weren’t the only producer of estrogen, researchers at the Wisconsin National Primate Research Center (WiNPRC) wanted to know how estradiol, the type produced by the hypothalamus region of the brain, affected the estrogen feedback loop.

This hormonal mechanism is the back and forth communication between the brain, pituitary gland and ovaries that regulates the menstrual cycle. The brain and pituitary gland tell the ovaries to produce estrogen. Estrogen then tells the brain and pituitary gland to release hormones. Those hormones then tell the ovary to release an egg. But after the discovery that the brain also produced estrogen, scientists at the Wisconsin National Primate Research Center wanted to know how these two sources of estrogen interact.

Using rhesus macaques as test subjects, they temporarily stopped their ovaries from producing estrogen. They also implanted a capsule under the monkeys’ skin that would release estradiol. The result? The brain and pituitary gland released only 30 percent of the luteinizing hormone necessary to begin ovulation.

Then, the researchers repeated the process, but this time, they blocked estradiol production in the hypothalamus. But without the estrogen produced by the brain, the hormones weren’t concentrated enough to release an egg.

“The ovarian estrogen starts the [hormone] surge, but the brain estrogen allows the surge to continue,” says Brian Kenealy, a researcher at the WiNPRC.

“This shows the brain’s estrogen is a huge helper, necessary for the release of an egg that makes pregnancy possible,” says Ei Terasawa, a pediatrics professor at the UW-Madison School of Medicine and Public Health and senior scientist at the Wisconsin National Primate Research Center. “We have to modify our concept of the feedback loop.”

For women struggling with infertility, this finding may unlock future treatments. For now, it’s a step forward in our understanding of the estrogen feedback loop.

Reviewed August 2019

The road to addiction recovery might become a little less rocky, thanks to a recent study by researchers at the Yerkes National Primate Research Center. Researchers suggest the drug fasudil, approved in Japan for cerebral vasospasm and stroke, could be an effective tool for treating drug abuse and preventing relapse.

Most of our everyday actions come from habits, not from deliberate decision-making. This can be detrimental in the case of drug abuse and drug-seeking behavior, says lead author Shannon Gourley, assistant professor of pediatrics, psychiatry and behavioral sciences at Emory University School of Medicine and Yerkes National Primate Research Center.

“Some habits are adaptive – for example, turning off a light when you exit a room – but others can be maladaptive, for example in the case of habitual drug use. We wanted to try to figure out a way to help ‘break’ habits, particularly those related to the highly addictive drug cocaine,” says Gourley.

She and former graduate students Andrew Swanson and Lauren Depoy first tested fasudil in situations where they had trained mice to poke their noses in two chambers, based on rewards of both food and cocaine. Then, the researchers changed the rules of the game – mice could now only get a reward from one chamber, instead of both. Fasudil helped the mice adjust and display “goal-directed” behavior, rather than their previous habit-based behavior.

Next, the researchers trained the mice to supply themselves a sweet cocaine solution. After the mice formed habit-based behavior, researchers changed the nature of that experience: the cocaine was paired with lithium chloride, making the mice feel sick. Fasudil treatment nudged the mice to give themselves less cocaine afterward, rather than continuing to respond habitually. Fasudil didn’t make cocaine itself less pleasurable, but was specifically modifying the habit process.

Unlearning habits involves remodeling connections made by cells in the brain. Fasudil seems to promote the pruning of dendritic spines, structures that help neurons communicate, by inhibiting Rho kinase, which helps stabilize cells’ internal skeletons. The drug thereby loosens the cell structures and appears to reduce the density of dendritic spines in the region of the brain important for learning new behaviors. Importantly, tests show fasudil must be directly paired with new learning to have that effect.

While overactive synaptic pruning has been proposed to play roles in Alzheimer’s disease and schizophrenia, when used appropriately, fasudil and similar compounds are promising candidates for drug addiction therapy.

Reviewed August 2019

The California wildfires of 2017 are shining a spotlight on research originally conducted back in 2008 at the California National Primate Research Center (CNPRC) which found that exposure to high levels of wildfire smoke negatively affects development of both the immune system and lung function.

Because the fires came so close to the UC-Davis campus where the CNPRC is located, researchers could test the effect of wildfire smoke on the center’s 5,000 nonhuman primates. Since they live outside, they’re exposed to higher levels of smoke than humans. Additionally, the timing of the fire in early summer coincided with the end of the birthing season for rhesus macaques, allowing the researchers to study the effects of the smoke on newborns.

Lisa Miller, leader of the CNPRC Respiratory Diseases Unit, and her team tested lung function and took blood samples from monkeys that were two to three weeks old during the 10 days of peak smoke pollution.

The fine particles found in wildfire smoke can lodge deep in the lungs and are known to cause respiratory illness. This research, however, revealed that exposure in infancy can also impair the development of the immune system. A sample group of the nonhuman primates that had suffered smoke damage were exposed to an infectious disease. Compared to a control group, the immune systems of the doubly-exposed nonhuman primates weren’t as effective at combating the virus.

“The idea behind this is that if we detected any changes in the animals this information might translate as a biomarker that can be used for kids,” said Miller. “The ability of the animals to respond to a real pathogen was reduced. It was a surprise and somewhat disturbing.”

With renewed interest in this research, Miller and others are pressing forward with their work.

Reviewed August 2019