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Fishing for new ways to stop Parkinson’s, a researcher makes big catches in the gene pool
Fishing for new ways to stop Parkinson’s, a researcher makes big catches in the gene pool
July 09, 2015
By Matt Windsor
When you hear the phrase “good genes,” you probably picture a supermodel like Kate Upton, or a sports superstar like Washington Nationals slugger Bryce Harper. People, in other words, who may have worked hard for their success, but were blessed with some helpful genes as well.
Superstar geneticist Haydeh Payami, Ph.D., has spent the past two decades searching for a different type of DNA. In a series of studies she calls “fishing expeditions,” Payami has been trawling the genome for bits of DNA that can help explain the mysterious patterns seen in Parkinson’s disease: Why do smokers have a much lower risk of getting the disease? What role does the immune system play in Parkinson’s? Why do some people get the disease in their teens, while it appears in others in their late 80s?
She has already had several intriguing catches. If you have the right combination of genetic variations, she explains, a few cups of coffee per day could reduce your Parkinson’s risk by an astounding 87 percent. With other sets of genes, a nicotine patch — or some daily ibuprofen, or probiotic pills — could do the trick. “If you could identify people who are genetically susceptible and tell them what to do, or what to avoid, maybe you can prevent the disease from happening,” Payami said.
It’s a perfect example of the potential of personalized medicine. But there’s more. Payami is now expanding her work to Alzheimer’s disease, and the same techniques could revolutionize the study and treatment of many other conditions.
The attractions of AlabamaPayami has a track record of success that includes several groundbreaking discoveries in Parkinson’s research. In 1994, “when the entire scientific and medical community thought Parkinson’s disease was purely environmental,” she said, her lab was the first to find a genetic component to the disease. “We are now at gene number 28 and counting.” Payami is the founder and leader of the NeuroGenetics Research Consortium, which has amassed 4,000 genetic samples and the most unique Parkinson’s data set of its kind on the planet. But to translate her findings from the lab to everyday life, she needs more samples, faster gene sequencing tools, more powerful computers and more scientific collaborators. And that’s why she left an enviably stable research position in New York, and a killer condo overlooking the Hudson River, for a new life in Alabama.
When David Standaert, M.D., chair of UAB’s Department of Neurology, brought Payami to Birmingham for a recruitment visit, he asked her repeatedly what it would take to get her to stay. “Finally, I said, everyone makes fun of me because in my CV I have written, ‘My 30-year goal is to have a prevention for Parkinson’s disease,’” Payami said. “I told him, ‘If you make that go to 15 years, I’ll come.’ And I think he did.”
With a new joint appointment at UAB and Huntsville’s HudsonAlpha Institute for Biotechnology — she is a professor of neurology at UAB and a faculty investigator at HudsonAlpha — Payami is doubling her DNA collection, and tapping into the latest genetic sequencing and analysis systems. She will add 2,000 patients and 2,000 healthy controls from UAB’s renowned Parkinson’s clinics, and have access to the world-class machines and analysts in HudsonAlpha’s Genomic Services Laboratory. “That will give us the power to do what we need to do,” Payami said. (Learn more about the Genomic Services Lab in this related story.)
Payami's gene samples will be sequenced on the Illumina HiSeq X Tens, the fastest gene sequencers on the market, in the Genomic Services Lab at HudsonAlpha. Each unit gets its own unofficial designation; this is Batman.
Payami and Parkinson's, by the numbersSix things to know about Haydeh Payami: She left her native Iran for the United States at age 19, a few years before the 1979 revolution, with one suitcase and not a single friend or relative in America. She has a great deal of energy. She carries her life’s work with her in two large freezers and a Tupperware container. She does not lack confidence. She has a master plan (several, actually) to stop Parkinson’s. She loves her daughter.
Six things to know about Parkinson’s: It is caused by a progressive loss of dopamine-producing brain cells, which affects movement and other bodily functions, although the exact causes of this cell death are still unexplained. It affects around 1 million Americans, and 60,000 more are diagnosed each year. The main treatment, l-dopa, was developed 50 years ago; even though it can ease the symptoms of Parkinson’s, it does nothing to stop the progression of the disease. In the past decade, a series of “neuroprotective” drugs has generated excitement; but all have failed in clinical trials.
The good news is that these drugs aren’t necessarily failures, Payami says. She has a plan to resurrect at least some of them (more on that later). But there are three cheap, widely available drugs that seem to be able to prevent and even treat Parkinson’s: caffeine, nicotine and over-the-counter anti-inflammatory drugs.
The protective power of a cup of coffeePayami makes her point with a jaw-dropping chart. “If you just ask people how much caffeine they drink and map that, you see that the risk for Parkinson’s drops by about 30 percent in heavy caffeine drinkers,” she said. It’s a pattern that epidemiologists have found in several studies, she points out. But Payami’s lab has been able to explore this relationship in an entirely new way. Her team scanned 7 million DNA variants from the genomes of 1,458 patients with Parkinson’s and 931 healthy matched controls, looking for genetic variations that set apart the heavy coffee drinkers who were protected against Parkinson’s from everyone else. (“Heavy” consumption, in this case, was around 2.5 cups per day and higher for 25 years.)
Her first hit was a gene called GRIN2A, out on chromosome 16. The most common form of the gene — the one that most of us have — doesn’t have a protective effect. But somewhere between a fifth and a quarter of patients in her sample have a mutated form of GRIN2A that dramatically alters their chances of getting Parkinson’s. “Their risk drops by 60 percent,” Payami said. Not only is this a fascinating finding for Parkinson’s researchers, but it has much larger implications, Payami points out. “This is the first demonstrated gene-environment interaction for any disease to come out of the modern whole-genome analysis.”
How it might workWhat could be behind that protective effect? GRIN2A produces a receptor for glutamate, an important signaling chemical in the brain. “Balancing glutamate on neurons is critical for neuronal toxicity,” Payami said. “And glutamate toxicity is one of the suspected mechanisms in the cell death we see in Parkinson’s. So you can imagine that if you have a problem with the receptor, your risk will be higher.”
After GRIN2A, Payami’s team found another link in the coffee connection: a gene called MAPK10. They discovered two protective variants in this case. One MAPK10 mutation, found in 31 percent of her study samples, confers a 60 percent drop in Parkinson’s risk; the other, found in only 2 percent of samples, brings a 75 percent risk reduction.
MAPK10 is an apoptosis gene — it helps regulate programmed cell death, the beneficial process that clears out damaged or unhealthy cells from the body. But apoptosis can go awry in several diseases, including Parkinson’s. “In animal studies, mutating MAPK10 completely protects against Parkinson’s,” Payami said.
“Many people will see no benefit, but for some people, it will drastically reduce their risk of getting Parkinson’s.”
Who might benefit?When Payami combined the data, she found that people who had the most common variants of both GRIN2A and MAPK10 — which is about 50 percent of those studied so far — received no Parkinson’s protection from coffee drinking. Another 40 percent of the people she studied had mutations that cut their risk in half. “And then there’s this lucky 7 percent, who have about an 87 percent risk reduction” when they consumed heavy quantities of caffeine, Payami said.
These are the people who should be drinking lots of coffee — or consuming a prescribed, regular dose of caffeine in pill form, perhaps. “Many people will see no benefit; but for some people, it will drastically reduce their risk of getting Parkinson’s,” Payami said. “We have to figure out the right dose, because too much caffeine can be harmful, even fatal.”
Two major, phase 3 clinical trials in humans are underway to gather more data on the effects of caffeine and nicotine on Parkinson’s. The investigators leading both trials are now “drawing blood on their patients, and we’re going to genotype them” at UAB.
Protection from nicotine, anti-inflammatory drugsPayami’s team has uncovered the same pattern among smokers. “If you divide people between those who smoked regularly and those who never smoked, there’s clearly a 25 percent lower risk of Parkinson’s disease among the smokers,” Payami said. But just as with caffeine, her team found large differences based on variations in a specific gene: in this case, SV2C. They have also identified a long, non-coding RNA behind the protective effect seen among people who regularly take anti-inflammatory drugs.
Two major, phase 3 clinical trials in humans are underway to gather more data on the effects of caffeine and nicotine on Parkinson’s. “These trials had already started when we discovered the genes,” Payami said; but she is now part of both. In one case, she sent an email to the principal investigator to ask if she could join in; in the other, “the PI came up to me to suggest a collaboration after a talk that I gave,” she said. The investigators leading both trials are now “drawing blood on their patients, and we’re going to genotype them here.”
If Payami’s genetic findings are borne out in clinical trials, it will be relatively simple to implement them in everyday medical practice, she notes. “All you’re doing is taking a saliva sample,” Payami said. “It’s a test that, if you’re doing it one at a time costs 50 cents, and if you’re doing it massively it’s less than a penny per person.”
The interior of a HiSeq X Ten sequencer
Here’s where you come in …The current clinical trials are testing caffeine and nicotine as treatments for Parkinson’s symptoms, Payami notes; they’re not examining preventive effects.
Payami has an ambitious plan to do that prevention trial, however. “We’d like to genotype tens of thousands of people who do not have the disease,” she said. “We want to follow them and see who is going to get the disease when, and who is not — and whether that is related to how much they smoked or did not smoke and how much caffeine they took or what kinds of diseases they had, whether they are using inflammatory drugs or not, and so on.”
After she discovered the two caffeine-related genes, “I started to call this my Starbucks project,” after a perfect potential sponsor, she says with a laugh. Now, with the addition of nicotine patches and anti-inflammatory agents to the possible preventive agents, the pool is much larger. “If companies bought into this, we could advertise it nationally and recruit tens of thousands of people to join,” she said. “They would each send in a saliva sample, and we could sequence their whole genome from that. Then they could go online every six months and update us on how they’re doing — as well as lifestyle factors, what they’re taking as far as inflammatory drugs, how much caffeine they are drinking, whether they are smoking.”
With a large enough sample, “you could have all the answers in five years, plus another few years to do the math and develop the algorithm that will say who would most benefit from caffeine, nicotine and anti-inflammatory drugs,” Payami said.
Danger in the “second brain”In another project, Payami’s lab is studying the link between Parkinson’s disease and the community of microbes in our intestines: the microbiome. The connection, she explains, is a protein called alpha-synuclein. “Deposits of alpha-synuclein in the brain are the hallmark of Parkinson’s disease,” Payami said. “But alpha-synuclein deposits first show up in the gut.” Because neurons reach all the way from the brain down to the gut, some researchers hypothesize that alpha-synuclein somehow becomes dysregulated in the intestines, then travels upward through the nervous system until it reaches the brain. “One clue is that constipation is one of the first signs of Parkinson’s disease,” Payami said.
She is now working with renowned microbiome expert Rob Knight, Ph.D., a biologist at the University of California-San Diego, and researchers at Emory University on a pilot study of 200 Parkinson’s patients and 150 controls. “It’s nearly complete,” she said. “We’re looking for a Parkinson’s signature in the microbiome of the gut. Then we’ll do a full-blown study with the 2,000 patients and 2,000 controls from UAB.”
Immunity and Parkinson’sOne of the Payami lab’s most significant discoveries so far revealed the role of the immune system in Parkinson’s. “Since the 1980s, people have been saying that the immune system is involved in Parkinson’s disease” in a causative role, Payami explained. “But others have said, ‘No, the immune system activity we are seeing is a consequence of the Parkinson’s, not the cause.’”
In one of her fishing expeditions, Payami’s team “pulled out HLA” — human leukocyte antigen, a group of genes that make the proteins that signal the immune system’s footsoldiers to destroy foreign cells. The discovery, published in Nature Genetics in 2010, “kind of nails the involvement of the immune system,” said Payami. She is now joining a UAB study led by neurology chair David Standaert on innate and adaptive immunity in Parkinson’s, and she plans to collaborate with HudsonAlpha faculty investigator Jian Han, Ph.D., a world-renowned expert in the immune repertoire, to search for other immune players in Parkinson’s.
“What I’m going for is you go in, get a finger prick, they put it on a slide and then slip it into a machine on the doctor’s desktop, and she can tell you, ‘Yes, you have Parkinson’s disease, and if we put you on l-dopa you’re going to develop hallucinations. So let’s put you on this other drug.”
Removing the trial and error of treatmentGenetic insights will also change the way that physicians treat Parkinson’s disease, Payami predicts. “Right now a patient comes in and it’s trial and error,” she said: “Will this drug work? At what dose? What kind of a drug cocktail do we make for them?”
Payami plans to join a study, led by Standaert, that is correlating patients’ genetic signatures with their response to l-dopa. Although this drug is still a cornerstone of Parkinson’s treatment, many patients develop an uncontrolled shaking, known as dyskinesia, after using l-dopa for anywhere from a few months to several years. Standaert “is trying to figure out if he can find a gene that makes some people develop dyskinesia where others don’t,” Payami said.
Ultimately, Payami wants to catalogue these gene-drug interactions for a wide range of Parkinson’s symptoms. “What I’m going for is you go in, get a finger prick, they put it on a slide and then slip it into a machine on the doctor’s desktop, and she can tell you, ‘Yes, you have Parkinson’s disease, and if we put you on l-dopa you’re going to develop hallucinations. So let’s put you on this other drug.’
“Or,” she continues, “my daughter can get tested and figure out if she’s at risk, and if she is, what can we do about it?”
Payami has several more active research areas, including this perplexing question: Why do some people develop Parkinson’s in their 20s, while others aren’t afflicted until their 80s? “What sets those people apart?” Payami wondered.
“If you could delay the age of onset by a few years, you could make a big difference,” she pointed out. Her lab has identified a gene variant that affects age of onset by eight years, but much more data is needed. With the additional patient samples from UAB and HudsonAlpha’s sequencing capabilities, “I want to do whole-genome sequencing of uncommon and rare variants affecting age of onset,” she said.
Delivering on the promiseEven as she forges ahead with Parkinson’s studies, Payami is also planning to reopen her investigations of the genetics of Alzheimer’s disease. “I started out in Alzheimer’s; but after the four major genes for Alzheimer’s were discovered, the field was at a standstill,” she said. “That’s why I moved to Parkinson’s.”
But now, with the advent of genomewide association studies, and the analytic tools necessary to decipher them, “I can go back,” she said. “I would like to take pharmacogenomics there, to look at genetic factors related to drug response in Alzheimer’s.”
The combination of collaborators, technology and expertise available at UAB and HudsonAlpha is a “dream come true” with potential applications to a host of diseases, Payami said. “This isn’t something you could accomplish at one institution; it’s going to take everyone working together to get a project like this done.”
The effort required is significant, but successful outcomes will be felt worldwide, she adds — and at home. “If we can have a prevention for Parkinson’s in 15 years, my daughter will be 39 and it will be perfect timing,” Payami said. “And I will be 74 and need better treatments. To me, this is a marriage of two fabulous opportunities. Now I have to deliver.”
Potential drug lessens neurodegeneration in Parkinson’s disease model
Andy WestThe first test in a mammalian model of a potential new class of drugs to treat Parkinson’s disease shows abatement of neurodegeneration in the brains of test rats and no significant toxicities, University of Alabama at Birmingham and Pfizer Inc. researchers report online in The Journal of Biological Chemistry.
At present, there are no therapies to slow or block the progression of Parkinson’s disease, a common neurodegenerative disorder that affects 7 million to 10 million people worldwide.
The rat model overexpresses the protein α-synuclein in one side of the brain. This leads to degeneration of the dopamine-generating neurons of the substantia nigra region of the brain.
“Because our observations were limited to a four-week period, we are not sure whether neurodegeneration associated with α-synuclein is truly prevented or just delayed,” senior author Andrew West, Ph.D., and colleagues wrote. “Either way, any interruption of neurodegeneration associated with Parkinson’s disease might represent a significant therapeutic advance.”
“For a patient with disease onset in the mid-60s, Parkinson’s disease runs its course over 10 to 15 years,” explained West, co-director of the Center for Neurodegeneration and Experimental Therapeutics, and the John A. and Ruth R. Jurenko Professor of Neurology at UAB. “So, if we can slow down the disease by even 50 percent, that may be effectively as good as a cure, given the available symptomatic treatments.”
The rat model used mimics two cardinal features of Parkinson’s disease: degeneration of dopamine neurons in the brain, and the accumulation of alpha-synuclein in surviving neurons. Patients with Parkinson’s have significant degeneration of dopaminergic neurons in the substantia nigra, up to 70 percent losses at even mid-stages of their disease, and abnormal accumulation of α-synuclein in many of the surviving neurons that occurs years earlier. Details of how Parkinson’s begins and how it progresses are still unclear.
|“For a patient with disease onset in the mid-60s, Parkinson’s disease runs its course over 10 to 15 years. So, if we can slow down the disease by even 50 percent, that may be effectively as good as a cure, given the available symptomatic treatments.”|
The model uses rats that express a cloned human G2019S-LRRK2 gene. Then these rats are injected in the brain (specifically a part of the brain called the substantia nigra) with a virus that expresses human α-synuclein. Test rats were fed the test inhibitor for four weeks, beginning at the time of infection. The small-molecule inhibitor easily passes through the blood-brain barrier to reach the brain from the bloodstream. Besides protecting against neurodegeneration, the inhibitor also lessened an inflammatory response by microglial cells seen in the brain in association with G2019S-LRRK2 expression.
West and colleagues also tested the inhibitor in outbred, wild-type rats, animals that are distinct from the strain that has the human G2019S-LRRK2. With the placebo, these rats showed about a 20 percent loss of neurons after four weeks of α-synuclein overexpression; but treatment with the inhibitor completely abated that loss. This result suggests that the inhibitor also has efficacy in the absence of the human G2019S-LRRK2.
“That is important because only 2 percent of Parkinson’s disease patients have the G2019S mutation,” West said. “These wild-type rats really excited us because it suggests the therapeutic action of the drug may extend to the majority of Parkinson’s disease patients. This has invigorated our collaborative efforts with Pfizer Inc. and the Michael J. Fox Foundation for Parkinson’s Research to invest more effort in LRRK2 inhibitors.”
The Pfizer inhibitor is one of a number of LRRK2 inhibitors under development by drug companies, and also at UAB in collaboration with the Southern Research Institute. West says there will be room for several different inhibitors if this class of drugs shows promise in initial clinical trials, which hopefully will occur within the next year.
The next steps for the Pfizer inhibitor will be testing a variety of doses and testing what happens if treatment begins after the α-synuclein expression has already started. West notes that any possible therapy for Parkinson’s disease will need to be incredibly safe because treatment would last for years.
“We have to be very careful with what our models can tell us,” West cautioned about extrapolating from the rat model. “We need to think critically about what type of benefit we can expect to see in humans because there are recent examples where improper clinical trial design have hindered the development of a new class of drugs for years and sometimes decades.”
For example, it is not clear where and how the inhibitor acts in the rat model, especially since inflammatory microglia cells in the brain also express LRRK2. Knowing such information might be critical to the success of these drugs in the clinic. In a separate trail of evidence, researchers, who include David Standaert, M.D.,Ph.D., have found that gene knockout of several neuroinflammatory processes can block α-synuclein neurodegeneration. Thus, the inhibitor may have an effect on just neurons or just microglia, or it may be a two-hit process affecting both neurons and microglia. Standaert is the John N. Whitaker Professor and chair of the Department of Neurology at UAB.
Co-authors of the paper, “LRRK2 Pharmacological Inhibition Abates α-Synuclein Induced Neurodegenerationα-Synuclein Induced Neurodegeneration,” are João Daher, Hisham Abdelmotilib, Xianzhen Hu, Laura Volpicelli-Daley, Ph.D., Mark Moehle and Kyle Fraser, all from the Center for Neurodegeneration and Experimental Therapeutics, Department of Neurology, UAB School of Medicine; Elie Needle, Yi Chen and Warren Hirst, of the Pfizer Neuroscience Research Unit; Stefanus Steyn, Pfizer Pharmacokinetics, Dynamics and Metabolism, Cambridge; and Paul Galatsis, Pfizer Worldwide Medicinal Chemistry, Cambridge, Massachusetts.
This study was supported by the Michael J. Fox Foundation for Parkinson’s Disease Research, the National Institute of Neurological Disorders and Stroke, and the American Parkinson’s Disease Association.