Ask an Expert: Dr. Farrer Answers Your Questions on the Genetics of Parkinson's Disease

Dr. Matthew Farrer, USC Professor of Medical Genetics, Canada Excellence Research Laureate in Applied Neurogenetics, and the Don Rix BC Leadership Chair in Genetic Medicine, is leading a global effort to discover new genes for Parkinson's and to accelerate the translation of these discoveries into new disease­modifying therapies. Dr. Farrer's lab has played a leading role in the discovery of every causal gene for typical late-onset Parkinson's disease (PD), and he has also identified some of the genes for atypical and early onset forms of parkinsonism.

Here are some of the highlights:

Alpha-synuclein (SNCA): Alpha-synuclein's role is to maintain neurotransmission (communication between nerves). However, the protein is also the major constituent of Lewy bodies (protein clumps) that build up in nerve cells in most patients with Parkinson's.

Leucine rich repeat kinase 2 (LRRK2): LRRK2 is an enzyme that is overactive in PD. Many rare mutations have been found in the gene which directly lead to familial Parkinson's. In addition, there are many genetic variants that present a risk for sporadic PD.

LRRK2 G2019S and G2385R: These genetic mutations are the most common mutations for Parkinson's disease, affecting hundreds of thousands of individuals worldwide.

Dynactin p150Glued (DCTN1): This gene is responsible for coding the protein complex called dynactin, involved in intracellular trafficking. Mutations cause Perry Syndrome, a rare familial and rapidly progressing form of Parkinson ism marked by hypoventilation (respiratory problems).

Vacuolar Protein Sorting 35 (VPS35 D620N): Mutations in this gene have been found to cause late-onset familial Parkinson's in at least 70 families. The protein is needed to sort, traffic and recycle many intracellular cargos including nerve cell receptors. The most important cargo that VPS35 recycles may be the dopamine transporter.

Glucocerebrosidase (GBA): One mutation in this gene is associated with risk of developing PD, but inheriting two mutant copies may lead to Gaucher's disease.

Receptor-mediated endocytosis 8 (DNAJC13): Identified in Canadian Mennonite families with late-onset Parkinson's, the protein encoded works cooperatively with VPS35.

Heat shock protein 40 (DNAJC12): Last year, Dr. Farrer's team discovered loss of this gene may cause early-onset, levodopa-responsive parkinsonism. Loss of the same gene may also lead to dystonia.

As a geneticist, how did you come to research Parkinson's disease?

I've been interested in brain health and disorders since I worked in hospitals and care homes when I was a teenager. I appreciated that physicians were at a loss to remedy these conditions, so I chose genetics as a way to understand them. Genes are the blueprint of life. I completed a degree in Biochemistry and a PhD in statistical and molecular genetics focusing on complex traits, i.e. disorders that are considered to be 'sporadic'. My early interests were in cognition and Alzheimer's disease genetics, but I quickly learned that Parkinson's had been inadequately studied so I thought there was an opportunity and need for my skills.

When I started in the field back in 1996, there weren't any genes implicated in Parkinson's disease. Our team has discovered a great many, and that has given us a rather unique perspective on what's going wrong at a molecular level and, as importantly, how we may be able to fix it.

What kinds of research are you currently working on? What are your methods?

There are two fields in genetics: association and linkage. Association is where you find there's a difference in one group compared to another. However, an association does not imply causation. To give an analogy: birds have beaks, but it's not the reason they fly. Nevertheless, birds and beaks are indisputably associated. With linkage on the other hand, that's where a genetic mutation is inherited with disease, and there is a causal influence. Namely, if you have the mutation, then you're likely to get the disease. Thus I've made linkage my foundation.

When I was a kid, my dad suggested I join the navy to see the world. I have navigated my career differently, still seeing the world but seen through genetics. For example, right now, I'm working with families in the Faroe Islands, a group of 19 islands inhabited by 50,000 people in the North Sea. There are 2-3 times as many people with Parkinson's in the Faroes as there should be, compared to neighbouring islands. It's such an isolated place, it has a well-defined boundary in terms of genetic variability and exposures, so I think it may tell us how genes and environment work together to cause Parkinson's disease.

I've also worked in Scandinavia for many years. It's where we originally discovered LRRK2 G2019S, in families with Parkinson's living in fishing villages along the Norwegian coast, and where we identified SNCA multiplications in Sweden, in the Lister peninsular. I have wonderful collaborations in Tunisia and Taiwan. In Tunis we found that 1/3 patients with Parkinson's disease (30%) have LRRK2 G2019S, and in Taiwan we found 1/15 patients (6%) have LRRK2 G2385R.

Once we've implicated a gene, the molecular neuroscience begins as we must study the effects of normal gene function and mutant dysfunction in the brain. Here we turn to mice, and precise genetic engineering, to make a model of each mutant gene. From these animals we learn what effects each mutation has on brain function and physiology, and more specifically on dopamine-related biology, from motor behaviour to neurotransmitter release. The genetic insights we've made are only because of the generous assistance of families around the world; they have become our foundation for subsequent research and our motivation.

What do these genetic findings contribute to our general understanding of Parkinson's disease?

Before 1997, we had no understanding of what was going wrong in PD on the molecular, or even cellular, level. We had no idea what was wrong within the cells of the brain and why dopaminergic cells were dying. Through genetics, we found an unbiased way of identifying those molecular pieces of the puzzle, if you like, that are essential and that in some families are faulty.

However, when we find a mutant gene, we don't understand how it leads to disease, we just know that it must. This leads us to ask questions like, how can individuals have a certain gene mutation all of their lives yet only go on to manifest Parkinson's at 70 years of age? How do they manage to mask all of these symptoms and signs? Why are their neurons susceptible? What are the molecular processes that patients where we've identified a particular genetic are happening?

It's my belief that if you're going to try to fix something, you had better first find out what's wrong. However, a real, true, understanding of what's going on, and how you might fix it, remains quite elusive in most neurologic diseases. Unfortunately, our medical system and our pharmaceutical industry see this as a long-term aim. Thus, in Parkinson's disease, there are no drugs that slow or stop disease progression as there are no drugs that target the underlying cause(s). Similarly, most neuroscience research is based on models, i.e. you have an idea, you set up experiments and control them as well as you can, and you test out your particular theory. However, the results are always going to be limited by the experimenter's question and the model they used.

My lab does it differently. First, with the help of patients and families, we look at human genome without any preconceived notion of what may cause the disease, of which gene it is, or what the mechanism involved might be. The mutant genes we have found have always been a major surprise. Our experimental questions and neuroscience are then "genetically-defined," and those mouse models are starting to reveal the precise molecular machinery perturbed, suggesting how we can fix it.

How can genetics help us develop ways to treat or prevent PD?

Medical genetics is about diagnosis, treatment and prevention. Our aim is to relieve symptoms by modifying disease progression. You can't turn back the clock, unfortunately, but I think we can develop ways to slow and perhaps halt disease progression - especially in risk- and that's a lot of patients right now.

Why should people with PD and their families support genetic research?

The federal and provincial funding landscape for Parkinson's research is complex. While these agencies are supportive, there are many competing healthcare issues; and their risk tolerance is relatively low. The same is true for industry. Philanthropic gifts enable high-risk, high-reward projects, and have enabled researchers like me to explore novel strategies, to get the data to be competitive for larger scale funding.

However, I'd also like to highlight that none of my innovation in the genetics of Parkinson's would have happened without patients and families contributing their DNA for research studies. I've been humbled by their support, and it has made me all the more determined to succeed in the science needed. Our efforts have been successful as genetic discoveries, and the molecular neuroscience based on it, have encouraged that large-scale investment in novel therapies. Many clinical trials are now focused on genetic targets, and aim to slow or halt disease progression. It has been incredibly gratifying to play a part in it.

This content was published in the Winter 2018 edition of our quarterly magazine, Viewpoints. The content was accurate as of this publication date.