The hunt for the parkinson’s gene

Just recently I found out that a close friend was diagnosed with Parkinson’s disease. I was shocked; not only had I always known her as a vibrant, energetic woman who practically lived at the gym, but until then I had associated Parkinson’s with aging, something people developed in their twilight years. I could clearly remember an elderly man with Parkinson’s whom I had visited at a local retirement home as part of my seventh-grade mitzvah project; his hands had trembled so forcefully that he could barely hold a cup. I also recalled the mother of one of my teachers, well into her eighties, who was confined to a wheelchair because after a fall—Parkinson’s had stolen her sense of balance—she could no longer walk. How could such a debilitating disease strike someone so young? So when my editor, Rechy Frankfurter, forwarded me the following email, I jumped at the assignment:

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Michael J. Fox Foundation leads the charge to study Parkinson’s genetics in Jewish populations Hi, there, I follow Ami’s coverage of Jewish news and relevant topics, and thought you might be interested in new genetic research into a common mutation among people of Ashkenazi descent and its relation to Parkinson’s disease. The Michael J. Fox Foundation for Parkinson’s Research (MJFF) is launching a new arm of their ongoing biomarker trial called PPMI to study individuals with genetic mutations associated with Parkinson’s disease (PD). One such mutation, on the LRRK2 gene, is much more common among Jewish people of Ashkenazi descent than the rest of the population, and has been identified as one of the greatest targets of interest in PD drug development. Researchers hope that a greater understanding of the biology of people with Parkinson’s or at risk to develop the disease will lead to new therapeutics and strategies to prevent disease onset. As you may know, certain genetic mutations more common among Jewish people of Ashkenazi descent can increase risk of diseases like Tay-Sachs, breast cancer and Parkinson’s disease. In order to develop more effective treatments and eventually cure these diseases, researchers are searching for substances, processes or characteristics of the body that signal disease risk, onset and/or progression, also known as “biomarkers” (like cholesterol level for heart disease). Biomarkers aid in diagnosis and disease management, and help researchers to test new drugs quicker by measuring biological changes rather than waiting for clinical improvement in their patients. There are no validated biomarkers for Parkinson’s disease, a reality PD researchers are hoping to change. I hope this is of interest. I can connect you with a spokesperson from MJFF, a PPMI investigator and a Jewish patient enrolled in the trial who can speak about why she’s participating in the trial and her experience so far. Best, xxxx

Michael J. Fox, the Hollywood actor, was diagnosed with youngonset Parkinson’s in 1991 at the age of 30. For seven years, he kept his condition a secret, until finally, in 1998, he came forward with his condition. That same year, he established the Michael J. Fox Foundation for Parkinson’s Research (MJFF), an organization that has granted more than $400 million to develop treatments for the disease, and ultimately, find a cure. Fox was far from the first public figure to become a champion of a very personal cause.In many cases, when these tragic conditions befall the famous, wealthy and well-connected, they often use their resources to finance research toward a cure. In many cases, they truly make an impact. Actor Christopher Reeve, for example, after a spinal cord injury that left him a quadriplegic, founded the Christopher & Dana Reeve Foundation, which funds research to cure and improve the quality of life for people living with paralysis. Thus far the foundation has raised $80 million. Cyclist and Tour-de-France champion Lance Armstrong started the Livestrong anti-cancer foundation after beating testicular cancer. The Livestrong  Foundation helps millions of cancer patients annually through research and support networks.The work Fox’s foundation does fills a great need, with five million Parkinson’s patients worldwide. Although the typical age of onset is 60 and older, people as young as 18 have been diagnosed with it.

One victim I spoke to said that when she was diagnosed with Parkinson’s at that age, she was “devastated. One moment I’d been a normal teenager, with nothing more important to worry about than whether I would pass my Regents. The next moment I faced a disability so terrifying I couldn’t bear to contemplate it. Then again, it would probably be just as painful to be diagnosed now, in my thirties, the mother of a family.” Kaila, a mother of two children who was diagnosed with Parkinson’s at the age of 35, referred to the disease as an “invisible terrorist” that took over her body. Now that people are living longer, receiving a diagnosis at a young age can mean having the condition for a significant portion of your life. In the medical world, Parkinson’s disease is referred to as a “boutique” disease because it manifests itself differently in each person. Some Parkinson’s patients are long-distance runners, while others are wheelchair-bound. Someone with Parkinson’s may be unable to button a shirt, while others can sew their own clothing. In middle or late stages of the disease, Parkinson’s patients can develop more unsettling symptoms like dyskinesia, involuntary jerking or flailing.

Sometimes, people will suddenly be unable to move (freezing), or they will experience festination, short, quick-paced steps that seem to accelerate involuntarily. However, these symptoms are not standard in every Parkinson’s case. According to the medical establishment, Parkinson’s disease is not fatal. “You die with Parkinson’s disease,” says the MJFF website, “not from it.” But, advanced symptoms can lead to complications that later cause death. Swallowing issues related to Parkinson’s, for example, may cause a patient to aspirate food into the lungs, which can cause pneumonia or pulmonary problems. Lack of muscle control or balance can lead to falls or fatal injuries. Again, each case is unique.British doctor James Parkinson was the first to identify the condition back in 1817, when he published his “Essay on the Shaking Palsy,” the first medical study on what would officially be known as Parkinson’s disease. Research since then has shown that the condition is the result of a breakdown in the central nervous system after cell loss in different parts of the brain.

One of these regions, called the substantia nigra, is the production center for the chemical dopamine, the neurotransmitter which, like a puppeteer, sends signals within the brain to coordinate movement. With low or no dopamine, neurons can go haywire, inhibiting the ability to control or direct the movement of one’s body.But what is behind the drop in cells? “That’s the million dollar question,” says Dr. Ken Marek, president and senior scientist at the Institute for Neurodegenerative Disorders who also serves on the MJFF’s scientific advisory board, with whom I was connected through the foundation. “We’ve been stymied each time we’ve tried to develop drugs to slow down the disease by a lack of knowledge about how [it] progresses.” As of now, the spectrum of opinion swings from environment on one end to genetics on the other. Some researchers believe that it is a combination of the two, depending on the person. Those in the environmental camp believe that exposure to toxins or chemicals, like pesticides, can contribute to the disease. A group of patients from California, for example, had all taken heroin contaminated with a substance called MPTP in the 1980s and later developed a form of Parkinson. Those who say that genetics are the culprit, however, have some significant research  data in their favor.

Now here is where things get really interesting. During the past ten years, there has been extensive study of the genetics of Parkinson’s. Working with a number of Parkinson’s patients and their families, a protein called alpha-synuclein was found to contribute to both the rare familial cases of Parkinson’s as well as the more common “sporadic” ones. This encouraged scientists to probe deeper into the role genetics plays in the onset of the disease. What they found was remarkable. “Parkinson’s is general. It doesn’t obviously run in families,” explains Dr. Marek. “But in some families, it does.” A single genetic mutation, most commonly in the gene known as leucine-rich repeat kinase 2 (LRRK2), has been identified in one to two percent of American Parkinson’s patients, which, according to Dr. Marek, is pretty common for a genetic mutation. But, there is one population in which the LRRK2 gene is present in 15 to 20 percent of Parkinson’s cases: Ashkenazi Jews. This discovery was, in Dr. Marek’s words, “extraordinary,” especially when combined with cases in Israel, where the LRRK2 gene is even more common. There, Parkinson’s is being designated as a genetic disorder because the risk is so much higher.

So how does this discovery parlay into a treatment, or, even better, a cure? The answer to this question is the driving force behind the Michael J. Fox Foundation’s newest project: The Parkinson’s Progression Markers Initiative (PPMI), an unprecedented, large-scale study of the connection between LRRK2 and the onset of Parkinson’s—and, most importantly, how it can be treated. A 32-clinical-site international study sponsored by The Michael J. Fox Foundation seeks to identify and validate biomarkers of Parkinson’s disease (PD). With a network of over 30 investigative teams, the organizers of the PPMI are seeking candidates for testing, specifically, individuals with Parkinson’s who are of Ashkenazi Jewish descent. The goal, says Dr. Marek, is to “understand the full range of Parkinson’s…so that we can be ready, when these treatment trials are available (hopefully, in the next two to three years) to target this population with therapies that are very specific to the problems that they have.” The study also includes Ashkenazi Jews who are related to someone with Parkinson’s and have the mutation, but not the disease. Even without Parkinson’s, it can still teach researchers quite a bit about the LRRK2 mutation’s “penetrance,” or the probability that it will lead to disease.

Drug companies are extremely interested in developing treatments focused on LRRK2 because, as an enzyme, it works like a switch, either on or off, which means it can be modified pharmaceutically. The question is, if you “fix” the LRRK2, does that have any effect on people who don’t have the mutation but do have Parkinson’s? “We don’t really know the answer to that,” says Dr. Marek, who is, incidentally, of Ashkenazi Jewish descent, “but it would certainly be important to the people with the LRRK2 mutation.” This means that these potential treatments may or may not apply to every case of Parkinson’s, because the cause is not universal. “We used to think of these diseases as a single entity,” Dr. Marek explains. “Now, in part because of genetics, we realize that while the endpoint is the same, the reasons why people develop this disease can be very different. So it’s useful to study different subsets of individuals who have different reasons for developing Parkinson’s and who may respond differently to medicines that may be targeted for those problems.” That said, those of Ashkenazi descent can now find out if they’re susceptible to the onset of Parkinson’s before it appears, through genetic testing. If you do have the LRRK2 gene, however, it doesn’t necessarily indicate that you’ll develop Parkinson’s. It simply puts you at a higher risk. “Then how, exactly, does the gene result in Parkinson’s?” I ask Dr. Marek. “It’s an uncertain question.

What we know is, if you have the gene, you’re at risk. But what we don’t know is why, for some individuals Parkinson sets in at an early age. [For example,] one family member [I worked with] who has the gene,  was stricken with the disease by age 50, while the 90-year-old mother with the gene is just fine. Why is that?” One woman helping Dr. Marek and the PPMI team to answer this question is Judy Wattenberg, a 70-year-old retiree from Tamarac, Florida. After an intro from the MJFF, Judy graciously told me a bit about why she chose to participate in the PPMI. Around ten years ago, Judy’s late mother was diagnosed with Parkinson’s disease, after experiencing tremors. Judy’s father acted as her primary caregiver, with Judy as backup, until her death. As she watched both of her parents struggle, she wondered if she was looking at her own future. Then, last April, Judy saw an article about the PPMI in the Sun Sentinel newspaper, which said they were looking for participants with a blood relative with Parkinson’s for the study taking place in Boca Raton. “I realized that anything your parents or your grandparents have, you’ve got a piece of it in your body,” says Judy. “There’s that old joke, ‘I inherited my father’s bad eyesight and high blood pressure.’ Now we have something else in the mix: Parkinson’s.” Judy felt that, after experiencing Parkinson’s up close, she had everything to gain by participating. “I can’t afford to give money to a charity at this point in my life, but if I can contribute something of me, that’s the most important thing.” Soon after, Judy called the contact for the study and had her initial meeting, where she was given basic information about the genetics of Parkinson’s.

A blood test was taken, which showed that she did, in fact, have the genetic marker the researchers were looking for: the LRRK2 mutation. Once the results were in, Judy went for another meeting, this time to undergo more testing. Everything that was found, she was assured, would be confidential, and if at any point she wanted to withdraw from the study, she was free to do so. Her visits continued. She went through many tests, including neurological testing, MRIs, DAP scans, written tests, memory exams, and even scratch-and-sniff tests, since many people with Parkinson’s lose their sense of smell. Friends asked her about her experience, thinking she was on some sort of medication. “When you mention to people that you’re going in for a study, they think you’re taking pills. But this has nothing to do with medicine; it has to do with diagnosing.” Judy has no regrets about joining the PPMI. “I’m very, very happy I got involved with it,” she says, so much so that when she relocates to Michigan, she will continue her participation there.

Not only is she happy to contribute toward the search for a cure, she admits she also has a “selfish reason” for joining the study: “I’ll be watched more closely for neurological changes, which is something your primary [physician] isn’t going to do.” But while she is positive about the outcome of the PPMI, she knows it is just one step on a much longer journey. “There are many paths to the end, so I’m hoping this is a good piece to the puzzle, to mix my metaphors,” Judy jokes. “Sometimes doctors diagnose by process of elimination; if a certain drug works, you must have Parkinson’s…If they can’t find a cure, but if they could diagnose much earlier, it would be wonderful.” To anyone who could be a candidate (including her own sister in Atlanta, who is going to have her blood tested) Judy says, “Do it. Definitely do it…We Jews are always into a charity. You have your tzedakah box, you do a mitzvah. To me, this is the biggest mitzvah going.” If you are interested in participating in the PPMI, visit html?ppmi-genetics.


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