Parkinson's Disease and Individualized Medicine
Wonderful article from the Mayo Clinics Online Research Magazine
High-tech advances in individualized medicine are helping Mayo Clinic researchers discover genomic causes of Parkinson's disease faster than ever.
In the 1980s, he began collecting blood samples from patients and volunteers, compiling family histories, and building up connections to hunt down the genes behind Parkinson's disease. It took him a decade to find the first gene.
Since then, more than a dozen genes have been discovered that play a role in Parkinson's disease, half of them by Dr. Wszolek and his colleagues at Mayo Clinic in Florida. In fact, scientists now believe that Parkinson's disease is primarily caused by genetic factors, with only a small percentage of cases stemming from environmental exposures.
Mayo Clinic researchers are using this newfound knowledge and the latest genomic technologies to further pinpoint more of the genes at fault and to illuminate the true causes of Parkinson's disease.
Early researchers seek environmental cluesThough it isn't clear when Parkinson's disease was first recognized, a number of ancient medical texts describe possible treatments for the disease's characteristic muscle rigidity, tremors and slowness of movement. Today, Parkinson's disease is the second most common neurodegenerative disorder in the United States, affecting about half a million Americans, according to the National Institutes of Health.
Although Parkinson's is a relatively common disease, there doesn't seem to be one common cause. Early research focused on possible connections between Parkinson's and environmental factors.
For example, many of the people who survived the 1918 Spanish flu pandemic went on to develop a virally induced form of Parkinson's known as postencephalitic parkinsonism. In the 1980s, people who had taken heroin contaminated with the neurotoxin MPTP developed a permanent form of parkinsonism that closely resembles Parkinson's disease.
Because of cases like these, researchers began looking for other environmental toxins that could trigger Parkinson's and found that people exposed to certain pesticides were at an increased risk, while tobacco smokers were at a reduced risk. By the time Dr. Wszolek was doing his residency, the Parkinson's disease research community was largely focused on uncovering more potential environmental factors.
A shift in focusBut then Dr. Wszolek's discovery led him down a different path.
"I came across a patient whose sister, mother and grandmother all had symptoms of Parkinson's disease," Dr. Wszolek recalls. "I asked myself, 'How could this person have such a strong family history if environmental factors were the sole cause? Perhaps the environment was playing a role, but couldn’t genetics be playing one as well?' "
Answering that question wasn't as easy as it may seem.
Dr. Wszolek traveled around the country, personally meeting with and examining his patient's family members to confirm their diagnoses. He eventually expanded the patient's family tree to more than 300 members and traced its origin back to colonial Virginia. Dr. Wszolek undertook similar endeavors with a number of other families affected by Parkinson's disease.
In part because of these efforts, he and his fellow researchers have identified a laundry list of genes — tau, alpha-synuclein, LRRK2, dynactin-1, VPS35, EIF4G1 and CSF1R — that can cause neurodegenerative disease. Dr. Wszolek and his colleagues have attempted to figure out how mutations in these genes set off the manifestations of Parkinson's disease.
Among these scientists is Owen A. Ross, Ph.D., a molecular biologist at Mayo Clinic in Florida. Dr. Ross' mentor, former Mayo Clinic neuroscientist Matt Farrer, Ph.D., had found that patients with one extra copy of the alpha-synuclein gene develop familial Parkinson's disease in their 50s while those with two extra copies — double the normal amount — develop the disease in their 30s. Dr. Ross then found that common variation in the alpha-synuclein gene could increase the risk of disease in patients with no family history — these were categorized as sporadic cases.
From a scientific standpoint, it made sense that if twice as much protein causes a severe form of Parkinson's and a 50 percent increase results in a moderate form of the disease, then perhaps a 10 to 20 percent increase would increase the risk of sporadic disease. These findings helped overturn the previously held belief that genes found in the rare cases of disease running in families weren't relevant to the more-frequent sporadic patients.
Conflicting theories about Parkinson's
Fluorescence in situ hybridization (FISH) showing alpha-synuclein (SNCA) triplication. At top, three copies of SNCA gene on one chromosome, and below, two copies of SNCA gene on one chromosome.
For instance, researchers have discovered that small clumps of protein molecules called Lewy bodies accumulate in the brains of people with Parkinson's disease. Researchers can't seem to agree about whether these clumps are protective or toxic. Some think the clumps act like a garbage bin, keeping all the protein aggregates in one place so that the rest of the brain cells can stay clean and function. Others think the presence of the aggregates themselves is toxic to the brain, eventually killing the cells that contain them. Still others think it is a combination of the two scenarios.
With researchers disagreeing on that fundamental point, deciding the true mechanism behind Parkinson's disease becomes even more complicated. But according to Dr. Ross, it is probably supposed to be that way.
"I think it may well end up being that many roads lead to Damascus. That there is a final endpoint, but that there are many different ways to get there," Dr. Ross explains. "You could pick any pathway that will lead to cell death — impaired protein degradation, mitochondrial dysfunction, increased inflammation — and say it's a potential cause of Parkinson's disease. Therefore, we need to start thinking about Parkinson's disease as a single set of symptoms with many different causes, and realize that there may be no single treatment or cure for everyone."
The rise of individualized medicine
Lewy body, the protein formation in a nerve cell in Parkinson's, also causes a form of dementia.
So Mayo Clinic created the Center for Individualized Medicine (CIM) to bring together physicians and scientists to explore how to use the latest genomic and molecular technologies to guide clinical practice. Alexander S. Parker, Ph.D., associate director of the Center for Individualized Medicine, and a neurology researcher at Mayo Clinic in Florida, says the center continues Mayo Clinic's tradition of research to help individual patients, but at a rapidly accelerated pace.
For example, a primary goal is to provide vital funding to Mayo Clinic investigators who are conducting research that could inform the next generation of personalized care.
The center recently awarded Drs. Wszolek and Ross and neurogeneticist Rosa Rademakers, Ph.D., of Mayo Clinic in Florida, a combined $50,000 grant to push their findings in Parkinson's disease toward the clinic. The researchers are creating laboratory models of the very same gene mutations that they discovered in patients and using them to test different chemicals, any one of which could eventually be found effective in treating Parkinson's disease and developed into a new medication.
"We try to make every investigator who gets CIM funding realize that we will fail if their work doesn't eventually end up in the clinic making a difference for a patient," Dr. Parker says. "That is different for a lot of investigators who are used to focusing on getting papers published or keeping their lab funded. Publications and grant funding are great, but the goal here is to change the way physicians practice medicine."
The Center for Individualized Medicine may be setting the bar high, but it is also building the resources and infrastructure necessary for researchers to take those next crucial steps. On the Florida campus, the center plans to increase bioinformatics expertise to analyze the vast amounts of data being generated, enhance biospecimen collection capabilities, and establish a biobank of samples from research participants without Parkinson's disease. The center also plans to open an individualized medicine clinic at Mayo Clinic's Minnesota and Arizona campuses.
Future challengesThese initiatives are helping investigators make new discoveries that are having a significant impact on a variety of human diseases, including other neurodegenerative disorders besides Parkinson's.
Last year, for example, Dr. Rademakers — supported by the Center for Individualized Medicine — uncovered a completely new genetic cause for amyotrophic lateral sclerosis (ALS) and also found that another gene associated with parkinsonism is a major risk factor for ALS. Likewise, Dr. Ross showed that a gene related to ALS may contain mutations that increase the risk of Parkinson's disease.
"Those studies have been an eye-opener, because suddenly we are seeing genes discovered in other neurodegenerative disorders that we didn't think had anything to do with Parkinson's disease, actually coming back and being risk factors for the disease," explains Dr. Ross, who collaborates with Dr. Rademakers.
Even when those risk factors are added to the dozen or so genes that have been identified at Mayo Clinic and elsewhere, they still only account for a small fraction — perhaps less than 5 percent — of the causes of Parkinson's disease. Dr. Ross thinks that ultimately as much as 90 percent of the disease risk may be attributed to genetics, with the rest related to environmental and other factors.
Although there is clearly a long way to go, Dr. Ross and his colleagues say that the latest genomic technologies, and the Center for Individualized Medicine support, are already making it possible to discover new genes faster than ever before.
Consider Dr. Wszolek. When he started his search in 1987, he had to collect blood specimens from about 25 affected people and hundreds of family members before he could start looking for the causative gene. Even after laying all that groundwork, Dr. Wszolek says he still had a hard time finding it.
For his latest discovery, he pinpointed a new gene using only three patients and 30 family members.
"The last 10 years saw enormous progress in the development of genetic technologies and that counts for a lot," Dr. Wszolek says. "It takes less effort, which is good because I want to spend my time finding more genes. My hope is for us to find these genes, understand them better, and then translate those findings in a way that gives families hope that we will be able to come up with treatments that work for them."