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Genetics and Parkinson's Disease


Genetics and Parkinsonís disease: What you should know and what you can do

Increased understanding of Parkinsonís disease genetics has breathed new life into PD drug development over the past decade ó and continues to form the building blocks for next-generation treatments. As participants in genetic studies, patients and their loved ones have a major role to play in speeding treatments based on promising genetic targets such as LRRK2 and alpha-synuclein. Learn about the role of genetics in PD and discover steps you can take today to become part of the genetics revolution under way in Parkinsonís research.


What You Need to Know about the Genetics of Parkinsonís Disease

The Genetics of Parkinsonís: Driving Treatment Breakthroughs in the Here and Now

Emerging evidence over the past 15 years has led researchers to believe that genetics plays a far greater role in Parkinsonís disease than was once thought. While only about five percent of people with Parkinsonís carry genetic changes that cause the disease, genetic research can ultimately pay off with treatment breakthroughs that would benefit everyone with Parkinsonís. ďPD genetic research is currently engaged in a period of major growth, and it is revitalizing every aspect of Parkinsonís drug development,Ē says Brian Fiske, PhD, vice president of research programs at The Michael J. Fox Foundation (MJFF).

Genetic research allows scientists to (literally) put Parkinsonís disease under the microscope and identify cellular mechanisms and machinery underlying disease risk, onset and progression. These findings apply to everyone with Parkinsonís, not just those with genetic mutations. MJFF is partnering with genetics researchers to gather vital intelligence about how the disease works, then hand it off to teams building on these discoveries to translate them into urgently needed new therapies to treat the disease.

Today there is a critical role to be played in PD genetics by patients and their loved ones, primarily by being genotyped and participating in clinical research. This is a personal decision, and an important one to discuss with oneís family and caregiver team. For now, learning your genetic status does not change your personal treatment regimen for PD. But by coming together in their thousands, people living with Parkinsonís today can make a significant contribution to Parkinsonís drug development and play a personal role in helping speed a cure.

Road Signs in the Right Direction

For years, it was widely believed that PD was caused by environmental factors, and that it did not include a genetic component.

Then, in 1997, researchers from the National Human Genome Research Institute discovered that mutations in a gene called SNCA were common in several families with a high prevalence of PD.† It was an intriguing discovery, as SNCA encodes for alpha-synuclein, a protein which clumps in cases of PD (regardless of the patientís genetic status). Since then, alpha-synuclein has remained a principal target for researchers working to develop new drugs for PD.

Following this study, the PD research community continued to make strides by studying the genetic make-up of large familial populations with high rates of Parkinsonís.† In 2004, two groups of researchers discovered a mutation in the gene LRRK2 that seemed to cause parkinsonism in several families in both North America and Europe.

Since this study and subsequent investigations like it, LRRK2 has emerged as the most common genetic contributor to PD discovered to date.

Grabbing the Reigns

As new research continued to support the idea that genes play a key role in Parkinsonís, the Foundation recognized the opportunity to play a defining role in driving forward genetic research that is often incredibly complex, and specific to small populations and even individuals.

In 2004, MJFF supported the first ever genome-wide association study (GWAS) for PD. Although studies in families were already identifying relatively rare mutations that could cause PD, the GWAS approach used new technologies at the time to look across a relatively large part of the human genome for common genetic changes that might increase peopleís risk for PD in general. The results of the study provided some of the first evidence that PD has no single Ďsmoking guní genetic link explaining the majority of cases. Subsequent larger GWAS, including a major collaborative Ďmeta-analysisí ( a method of integrating and analyzing data from multiple studies) supported in part by MJFF, have since found a handful of genes that may explain some risk for PD.† The main takeaway from these studies is that Parkinsonís is a complex disease with multiple potential causes. As new technologies allow researchers to navigate this genetic Ďmapí with even greater precision, new insight into the underlying causes of PD and potential therapeutic targets continues to grow.

To this end, the Foundation believes that current efforts should focus on identifying the combinations of interacting genetic and environmental factors that can lead to the disease, keeping in mind that what contributes to the disease in one group of people may not necessarily contribute in another group. Despite this complexity, understanding the genetic factors involved in Parkinsonís remains a critical need, as this can point to underlying pathways involved in the disease process and ultimately reveals new targets for drug developers.† More and more, scientists are identifying different genes that cause PD, but that are beginning to point to converging pathways in the brain, pathways that could be targets for new drugs.

By bringing together researchers, physicians and drug developers around novel discoveries to share information in a pre-competitive space, the Foundation aims to get closer to answers about what might work as a genetics-driven treatment for PD.

"It's important that the Foundation, and other stakeholders, try to bring their resources to bear on getting geneticists interested in PD research onto the same page and into the same room as neurologists who see patients," says MJFF SAB member Mark Cookson, PhD, of the National Institute on Aging. "It is critical that these groups talk early and often about the next steps in genetic analysis and, in the longer term, in moving from genetic discoveries to practical treatments."

Rogueís Gallery: Zeroing in on the Most-wanted Genetic Suspects in Parkinsonís Disease

In 2012, MJFF is employing this collaborative spirit toward finding therapies for PD based on genetic targets, devoting the lionís share of its gene-based investments to alpha-synuclein and LRRK2 (Other important genetic targets in PD include tau, which also plays a role in Alzheimerís disease, and GBA, which is implicated in Gaucherís disease).

Thanks in part to MJFF investment and thought leadership, biotechs Signum biosciences and Proteotech, signed synuclein-based drug development deals with GlaxoSmithKline in early 2012. Vienna-based biotech AFFiRiS AG is partnering with MJFF to test a first-of-its-kind PD vaccine focused on clearing alpha-synuclein clumps from the brain. †The AFFiRiS trial will engage 24 subjects with mild Parkinsonís disease over two years. The first participants were enrolled in March.

And with leadership funding from the Brin Wojcicki Foundation, MJFF is pioneering a four-pronged approach to LRRK2 in an effort to streamline and orchestrate drug development around the gene. By bringing research groups together early on, and encouraging them to share resources, troubleshoot common problems and identify best resources, the Foundation aims to speed collective efforts to move LRRK2 toward practical therapeutic relevance for patients.

The Choice to Get Genetically Tested

In order to continue to move forward with promising genetic targets, researchers will need volunteers to step up and be willing to participate in genetic studies. Thereís a big reason to get genetically tested if you are so inclined, says Foundation Scientific Advisory Board member Andrew Singleton, PhD:

ďYou are part of something very important ó a research strategy that could help speed new and better treatments for a wide range of diseases, including Parkinsonís.Ē

Of course, deciding whether or not to get genetically tested is a nontrivial decision.

In certain cases of PD, there is mounting evidence that people with particular gene mutations may be at higher risk for Parkinsonís disease, especially if the disease runs in your family and you stem from certain populations (e.g., Ashkenazi Jewish). However, none of the genes implicated in PD demonstrate 100% Ďpenetranceí; in other words, just because you have the gene mutation does not mean you will get the disease.

Furthermore, there are no proven treatment options for people who fear they are genetically at risk for PD: This is currently no therapy that has been shown to prevent PD or slow its progression. Although there are a number of companies seeking to sell genetic testing for PD, it is important to understand that the information you receive from these tests will not be very informative at this stage. Individuals seeking these tests should consult with qualified genetic counselors both before and after receiving their results in order to understand all of the issues involved.

Still, while knowing your gene status may not necessarily offer you early treatment options, it can help more generally with efforts to understand PD and develop new treatments. Most progress in genetic research related to PD has been made through large-scale studies of familial populations with similar genetics: By analyzing large pools of similar data, researchers can home in on shared characteristics that play a role in disease.

Gary Schmitz, 50, who was diagnosed with Parkinsonís at age 38, didn't think twice. "For me," he says, "the question was why wouldn't you want to contribute?" He joined the 23andMe Parkinsonís Disease Research Community in January 2010. He learned he was at only a slightly higher than normal risk for developing PD, something of a relief, since he now worries less about his two children developing Parkinson's. Knowledge is empowering either way, he says. "If you're at risk for something, then you can do something about it. You may know you need to see a certain type of doctor twice a year versus once."

Action Plan: What You Can Do Today

Most clinical research into the genetics of Parkinsonís focuses on the LRRK2 mutation because there are more known populations of people with this risk factor.

The Parkinsonís Progression Markers Initiative (PPMI) is recruiting individuals of certain descent ó Ashkenazi (Eastern European) Jewish, North African Arab Berber and Basque ó who have Parkinsonís or have a relative with Parkinsonís. PPMI is a study to identify Parkinsonís biomarkers: objective measure of disease risk, onset or progression. Individuals from those groups are eligible for testing for the LRRK2 genetic mutation at no cost. Based on the results, some individuals will be invited to undergo further evaluation and participate in the five-year study.

For more studies looking at LRRK2 mutations ó or for all Parkinsonís research studies ó visit Fox Trial Finder. You can search for studies and/or make a profile and be matched with clinical studies in your area that you may be interested in.



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PPMI, MJFF's flagship study, is studying the connection between PD and the LRRK2 gene and needs volunteers.

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The MJFF Parkinson's Podcast Series pairs host Dave Iverson with Parkinson's researchers to talk about the latest scientific understanding and therapies in development.

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