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LRRK2: The Greatest Known Genetic Contributor to Parkinson's Disease

What is LRRK2?

Discovered in 2004, LRRK2 is the greatest known genetic contributor to PD.

By and large, PD is not considered to be a genetic disease. The majority of cases are called idiopathic, which simply means that we don't know what caused the disease. In fact, only about 10 percent of PD cases so far have been linked to a genetic cause. Mutations in the LRRK2 gene are the most common cause of PD in this relatively small group, representing one to two percent of total Parkinson's cases.

However, for people of two particular ethnic backgrounds — Ashkenazi Jewish and North African Arab Berbers — mutations in LRRK2 account for a much greater number of PD cases than in the general population. While estimates vary, it is believed that changes in LRRK2 (predominantly the mutation scientists know as G2019S) account for 15 to 20 percent of PD cases in Ashkenazi Jews and about 40 percent of cases in North African Arab Berbers. Other genetic changes in LRRK2 that increase PD risk have been found in additional populations, such as in Asians of Chinese descent. It remains an active area of investigation to find all the genetic changes in LRRK2 that may lead to PD.

Why is LRRK2 a priority for MJFF?

Genetic targets allow us to study important mechanisms underlying disease onset and progression. By studying LRRK2 we can speed progress toward treatments that would benefit everyone with the disease, not just those with genetic mutations.

To appreciate how scientists target LRRK2 to develop better Parkinson's treatments, it is helpful to understand some basic biology:

The genes in our DNA tell our bodies how to manufacture molecules called proteins that help body cells carry out their intended functions. When researchers talk about LRRK2, they may be referring to the LRRK2 gene or the LRRK2 protein.

Think of the gene LRRK2 as a recipe — let's say it's a recipe for apple pie. The cell reads the LRRK2 gene's "recipe" to make the "pie," which is the LRRK2 protein. Mutations in LRRK2 are like errors in the recipe — ½ teaspoon of cinnamon instead of ¾ — small problems, but enough to make the pie come out wrong.

Just as there are different kinds of pie, there are different kinds of proteins. The LRRK2 protein belongs to a class of proteins known as kinases. These proteins work in the cell by chemically altering other proteins, an important mechanism that cells use to switch on or off various biological processes.

In Parkinson's disease caused by mutations in the LRRK2 gene, the LRRK2 protein ‘kinase' appears to be slightly overactive. This may actually be a good thing. Drug makers are very skilled at developing so-called "kinase inhibitors" — drugs that can help to offset kinase overactivity. A LRRK2 kinase inhibitor could improve the function of the LRRK2 kinase to prevent Parkinson's from arising or progressing.

Pharmaceutical companies have a great deal of experience (primarily from cancer research) making drugs that target and inhibit kinases. For this reason, companies have a strong interest in furthering such products. While there are no specific drugs in clinical testing that are inhibitors of LRRK2 yet, several companies are actively pursuing LRRK2 therapeutic research and development.

How is MJFF working to speed development of practical treatments based on LRRK2?

MJFF is pioneering an innovative approach to LRRK2 in an effort to streamline and orchestrate drug development around the gene. Our goal is to bring research groups together early on — sharing resources, troubleshooting common problems and identifying best resources — to speed collective efforts to move LRRK2 toward practical therapeutic relevance for patients.

• The Foundation is funding a large LRRK2 Biology Consortium to test critical hypotheses about both normal and pathological LRRK2. This collaborative network of more than 30 investigator teams will help researchers understand LRRK2's structure and function in order to identify drug candidates that can modify its activity in the body and the brain.
  
  
• We are concurrently assembling groups of people with LRRK2 mutations and their family members all over the world who can be studied by doctors, so that the field will better understand the nature of Parkinson's clinical features in the presence of LRRK2. By studying people who carry the LRRK2 mutation and do not have PD, we may also learn about the very first signs of disease that could be used to detect PD even earlier than we can today. This will set the stage for more efficient clinical trials once candidate drugs are found, and for determining how to design a drug for LRRK2 parkinsonism that will also help people who do not have the mutation.
  
  Currently, the LRRK 2 Cohort Consortium, which is made up of eight separately funded groups studying 3,000 individuals across 20 clinical sites, is employing clinical and bio-specimen collection methods to establish a valuable resource for continued study of LRRK2-linked parkinsonism. Consortium scientists can access shared clinical data at a database managed by the University of Rochester Clinical Trials Coordinator Center. With leadership from MJFF, sites from the United States, Canada, China, Germany, Israel, Norway, Spain and Tunisia are sharing results with each other.
  
  
• At the same time, the Foundation is leading the development and distribution of critical research tools such as pre-clinical models and laboratory reagents, which remove hurdles for investigators to effectively study LRRK2 and test new hypotheses about how to exploit its weaknesses for patients' benefit. Partly due to competition within the research community to understand LRRK2, and due to restrictive patents, there is traditionally limited sharing of tools and resources. MJFF has created a new model, developing many of these tools ourselves, in order to make them more freely available to the researchers who want them with fewer restrictions.
  
  
• The Foundation also plays a convening role to ensure that the pharmaceutical industry's expertise is being leveraged in the pursuit of LRRK2-based therapeutics. Industry's perspective is critical if we are to efficiently make drugs for LRRK2. For example, mounting a clinical trial to test a LRRK2-based therapeutic would require both the therapeutic itself and other resources, such as imaging markers that can indicate the effectiveness of the candidate drug. The LRRK2 Industry Advisory Group, which includes Pfizer, Lundbeck, EMD Serono, Genentech, Elan, and Eli Lilly, among others, is coming together with MJFF in a precompetitive space to discuss how to best create and share these kinds of resources, in moving forward to develop LRRK2 targeted drugs.

Google co-founder and MJFF supporter Sergey Brin has taken a very proactive approach to the knowledge that he carries the mutation of LRRK2. When does it make sense to get tested for LRRK2, and how might one react to the knowledge that one is a carrier of the mutation?

The decision to have one's genome tested is a nontrivial and personal one. The chances of having a genetic form of PD are fairly low. If you have a long history of PD in your family, especially if you come from an ethnic background with a greater prevalence of the LRRK2 mutation , there might be some value in genetic testing.

Still, in the overwhelming majority of PD cases, we cannot identify a single clear-cut cause. Moreover, even if you found out that you carried a genetic mutation related to PD, there's no action plan for preventing PD or treating it differently because you have the mutation.

As we understand more and more about genetics and PD, we are able to make more refined decisions about who should or should not be tested. Since 2009, MJFF has been funding a partnership between 23andMe and the Parkinson's Institute and Clinical Center, a novel attempt to leverage DNA technology, the Internet, and patient participation to enhance scientific understanding of Parkinson's disease and the field's ability to develop breakthrough treatments.

Since genetic testing confirmed that Brin, who has the disease in his family, is at a higher risk of developing the disease, he has adopted a proactive stance toward dealing with this risk. In addition to supporting MJFF, in 2010 he told Wired magazine that he believed he could cut his risk in half through diet and exercise. Certainly, it doesn't hurt to work out more and eat better. For now, this seems to be the best way to combat genetic predispositions to a variety of potential health conditions.

August 2011