News in Context: Canadian Mennonite Family Stands Up For Parkinson's Research Helping to Link New Gene to PD
Recently, a team of geneticists led by Michael J. Fox Foundation (MJFF) Scientific Advisory Board member Matt Farrer, PhD, found the latest gene to be implicated in late--onset forms of Parkinson's disease (PD).
Farrer's team, from the University of British Columbia, Vancouver Coastal Health and including University of Saskatchewan neurologists Drs. Alex and Ali Rajput, made the discovery thanks largely to the long--standing and generous investment of a Canadian Mennonite family of Dutch--German--Russian ancestry.
MJFF spoke with Farrer and Foundation VP of Research Programs Brian Fiske, PhD, to learn more about the link between PD and a mutation in the gene, called DNAJC13, and what this latest discovery, and others like it, might mean for finding better treatments for the disease. Farrer also discusses the unique commitment to science made by this family, which came together from across Canada in the name of research.
NOTE: The medical information contained in this article is for general information purposes only. The Michael J. Fox Foundation has a policy of refraining from advocating, endorsing or promoting any drug therapy, course of treatment, or specific company or institution. It is crucial that care and treatment decisions related to Parkinson's disease and any other medical condition be made in consultation with a physician or other qualified medical professional.
MJFF: Tell us more about how this study came about.
MF: This particular family has been involved in research for 28 years. They first agreed to participate because of the high prevalence of PD in their family -- six brothers all developed late--onset PD which is unusual.
In 2007 Farrer's team took on the project to identify a new genetic mutation that might provide clues about PD. After some years of effort and using powerful new technologies in gene sequencing, they were able to significantly narrow down the search for such mutations. A human strand of DNA is made up of six billion nucleotides (individual molecules that comprise our DNA) -- the study had highlighted three potential variants that might lead to PD, but the team needed additional help to zero in on one culprit.
In 2012, about 70 family members gathered for a reunion in a church hall on the outskirts of Saskatoon. They'd come from several provinces across Canada. I talked to them about genetic research and how far we have come identifying the molecular basis in PD. I explained that further participation would mean a lot for science and humanity, and would ultimately lead to better treatments to PD. It was daunting to instigate a scientific rather than a medical discussion, with a religious group. However, their reaction was quite humbling. One after another the patriarchs stood up and announced that they would consent to take part. By the end of the afternoon, basically everyone had a brief clinical exam and provided a blood sample.
MJFF: What exactly did you learn from this Mennonite family?
MF: This particular study engaged 57 members of a family from Saskatchewan -- 12 of the participants had already been diagnosed with PD. Using a technique called massively parallel DNA sequencing, we were able to study the genetic make--up of these volunteers, which led us to find the new mutation in a gene called DNAJC13. We then corroborated these findings in other members of this family from across Canada.
MJFF: What is 'massively parallel DNA sequencing?'
BF: Massively parallel DNA sequencing is one of the technological breakthroughs allowing researchers to read large stretches of human DNA more rapidly and cheaply than ever before. It relies on a basic concept of breaking DNA up into many smaller fragments and then sequencing each of those fragments at the same time (in parallel). A computer can then stitch all of these fragments together again quickly to give you the complete DNA sequence.
MJFF: Does a mutation specific to a particular family like this one offer insight into Parkinson's disease on the whole?
BF: Any time we can learn more about the machinery of our brain and how changes in it may cause disease, we are learning valuable information. While it's too early to know if mutations in the same gene will be seen in the broader PD patient population, what is interesting here is that Dr. Farrer and his team have found a mutation that points to one mechanism by which PD may be triggered. In this case, the DNAJC13 gene is involved in a major process for trafficking membrane--associated proteins from one part of the cell to another. If this recycling process is disrupted it could lead cellular dysfunction and potentially cell loss.
MF: By analogy the role of genetic discovery in developing treatments for diseases like PD is rather like trying to fix a car when the engine refuses to start. The first step to getting it running is to have a rudimentary understanding of what the different components of the engine do -- the battery, distributor, spark plugs, valves, pistons etc. -- and how these components work together. While susceptibility to PD may vary according to individual -- whether it's the battery or spark plugs etc -- the overall system perturbed, the engine, is likely to be similar in all patients. The "molecular machinery" discovered through human genetics provides novel targets for new, more effective treatments.
MJFF: What are the challenges to identifying genes linked to PD and translating those into therapies?
BF: We still have a ways to go to. It's a major challenge: How do we interpret the expansive amounts of data culled from new, cheaper, and more accessible technologies such as massively parallel DNA sequencing, and then find concrete ways to turn these analyses into drugs? There's a long road ahead.
The good news is that progress is already being made: New findings in the past few years, such as Dr. Farrer's latest discovery, continue to provide critical information as to mechanisms underlying PD that could one day be targeted with potential drugs. The Fox Foundation is bringing together scientists engaged in early stage biological research with clinicians and industry to streamline the drug development process around genetic targets, in particular LRRK2.
To learn more about genetics' burgeoning role in PD drug development, check out the content on our genetics priority area Web page.