By Matthew Farrer, Ph.D.
A decade or so ago, medical textbooks and most practicing neurologists held the view that Parkinson’s disease (PD) occurred sporadically. Environmental toxins, such as pesticides, were considered the most important risk factors, despite the difficulty in measuring a person’s lifetime exposure. In contrast, genetic risk factors were thought unlikely, given that Parkinson’s disease rarely affected identical twins at the same age. Researchers debated the issue for several decades until genetic studies revealed that the DNA we inherit contributes to our susceptibility for Parkinson’s disease.
In contrast to environmental exposures, an individual’s DNA can be reliably measured. Using modern technologies, scientists are able to study the genes of families as well as thousands of individuals. More than 20 regions of the human genome have been found to be “associated” with Parkinson's disease, and in many of these, “causal” gene mutations have been identified.
Mutations that are “causal” lead to inherited disease down a family line. These are found in only about one to two percent of people with Parkinson’s. By contrast, those variants that are “associated” — also known as “common variants” — do not directly cause Parkinson’s but contribute to disease susceptibility. While the contribution is modest for an individual, the risk that may be attributed across
a population is considerable.
Together, these genetic discoveries provide a “molecular foundation” on which to build novel treatments for Parkinson’s. The rationale is as follows: if we can determine what it is that causes the problem, or what it is that predisposes individuals to disease susceptibility, we can develop more effective medications to tackle the symptoms and to slow — and perhaps to halt — the progression of Parkinson’s.
What Does Genetics Mean to Your Family?
About 14 percent of people who have Parkinson’s have a first-degree relative — a parent, sibling or child — who also lives with Parkinson’s. The medical literature includes evidence of many large families in which there are multiple members affected by Parkinson’s, often spanning successive generations.
Traditionally, a method called classical genetic mapping allowed us to identify rare mutations in genes that result in disease. The first of these to be described in Parkinson’s was in SNCA, a gene that makes a protein named alpha-synuclein. This mutation is the result of a single DNA nucleotide change, “c.209G>A (A53T)” — in effect a single spelling error among six billion such nucleotides in the genome (see call-out box below at right). It was first found in a family from Italy in which many members through several generations developed Parkinson’s.
Although the A53T mutation is rare, what we learn from it can be applied to more common cases of Parkinson’s. For example, alpha-synuclein was found to be the major component of protein clumps known as Lewy bodies, affecting the nervous system of this family and the majority of people with Parkinson’s. The presence of Lewy bodies in the brain is now considered the hallmark of Parkinson’s. Alpha-synuclein also led to the discovery of common “associated” variants in this same gene in populations all over the world.
In another example, a mutation in a gene called LRRK2, “c.6055G>A (G2019S),” was found in the DNA of one-third of people with Parkinson’s in Northern Africa, one-seventh of people with Parkinson’s with Jewish heritage, and one in a hundred people with Parkinson’s in North America. It encodes a protein known as leucine-rich repeat kinase 2. Interestingly, the majority of those who carry the G2019S mutation are genetically related to a common ancestor, regardless of current citizenship and geographical location. Recently, many more common LRRK2 variants have been found in populations around the world. Some of these are believed to increase risk for Parkinson’s, while others appear to protect against it.
Recent technological advances in a process known as “massively parallel” DNA sequencing have made it possible to quickly and cost-efficiently conduct family-based genetic discovery and to identify novel, rare mutations. The first discovery in Parkinson’s using this method was a mutation in the gene called VPS35, “c.1858G>A (D620N),” and was funded in part by the Parkinson’s Disease Foundation. VPS35 encodes a protein known as “vesicular protein sorting 35” (see image on page 7). Its responsibilities within the cell include managing a “recycling system” for membrane-associated proteins. Nerve cells have more membrane and surface area than other cells, which they need to maintain and repair during neurotransmission and aging.
As with all mutations, understanding the role of VPS35 — in this case, as part of a recycling system — could provide clues to what is causing Parkinson’s.
What Does Genetics Mean to Individuals?
The majority of people who have Parkinson’s, about 86 percent, do not have a close family member with Parkinson’s. Among these individuals, Parkinson’s may not have been inherited, but genetic factors have been shown to contribute to their susceptibility.
This discovery has in large part been due to the development of “genome-wide association studies” (GWAS, for short). GWAS involve thousands of people with Parkinson’s, and have helped to identify the common genetic variants mentioned above. The technology applied in GWAS cannot meaningfully predict an individual’s risk of developing PD. However, findings from these studies have repeatedly demonstrated that among people with Parkinson’s, there are relatively common variants within specific genes — and often regions of the genome (or loci) that contain several neighboring genes — which contribute to disease risk.
In Caucasian populations, GWAS in Parkinson’s have shown that two genes in particular — SNCA, which makes alpha-synuclein and MAPT, which makes the protein tau — are most important. (You may recall that we mentioned SNCA earlier as it may harbor causal mutations in certain families.) GWAS studies in non-Caucasian populations have taught us that the genetic contribution to Parkinson’s in different countries, and among various ethnicities while overlapping, may be different. For example, in Japan, a gene region found on chromosome 1, known as PARK16, was found to be more prominently associated with Parkinson’s.
Ever-larger GWAS and analyses are being planned to identify additional genetic components associated with Parkinson’s risk, albeit playing an ever-diminishing role. Such studies will compare the DNA variability in several hundreds of thousands of people who have Parkinson’s with age, gender and ethnically-matched individuals who do not. These findings do not tell us about the risk for Parkinson’s that is faced by any one individual.
Nevertheless, the findings in aggregate, in a given population, help identify the many molecular components that are disturbed in Parkinson’s.
To age “successfully,” biological systems must work optimally. The discovery of genetic mutations and variants tell us which parts of the genome, and which molecular components of a nerve cell in a person’s brain, are critical to keeping systems working properly and which go awry in Parkinson’s.
Completing the Genetic Puzzle
Through this process of genetic discovery a common theme appears to be emerging in the biology of Parkinson’s — just as the picture on a jigsaw puzzle begins to take shape as the pieces are filled in. Each new gene and story the genes tell together are providing the most remarkable, most fundamental, molecular insights into what is happening in Parkinson’s disease.
For example, we know that the genes implicated in Parkinson’s coordinate interconnected processes. Alpha-synuclein (SNCA) regulates the delivery of certain molecules (including neurotransmitters), responsible for communication between one nerve and another. Within the cell, tau (MAPT) helps regulate the loading/ unloading of these molecules and other “cargo” on both local and long distance highways. Tau manages the back and forth journey of the cargo — the frequent stops and loading/unloading that
a delivery van might make.
Meanwhile, LRRK2 and VPS35 select and sort cargo like workers in a mail depot, ensuring they are appropriately packaged and addressed to get to the right place.
Through genetic discovery, we are beginning to understand how minor imperfections of very specific and related biologic processes, possibly accelerated by genetic mutations or disease-associated variants, become a chronic and cumulative problem. We must continue to find more pieces of the puzzle, and to understand how they are related. The clearer the picture, the higher its molecular resolution, the more likely we will succeed in future therapeutic development.
Genetics and New Treatments
In all areas of medicine, genetic discovery is helping to predict and prevent, to make pharmaceutical investment and interventions more successful. Findings such as the mutations and variants mentioned above point us to specific targets to treat. Knowing the genetic background for disease susceptibility in individuals will improve the design of clinical trials and the likelihood of success.
A mutation in VPS35 in a nerve cell
In Parkinson’s, the slowly progressive course provides the timeframe in which new medications, if appropriately targeted, can be efficacious. Already there are numerous translational research programs focused on turning discoveries such as alpha-synuclein and LRRK2 into medications.
Challenges remain — for example, in the development of biomarkers that will track the progression of Parkinson’s and provide benchmarks to measure the effectiveness of treatments. But the pace of progress is quickening. Most encouraging is that the separate pieces of genetics research are now being brought together, providing an undisputable molecular foundation upon which to build the medications of tomorrow. Indispensable to success is the participation of people with Parkinson’s and their families in genetic research, their gift to humanity.
As we “join the dots,” so the biological network that is perturbed in Parkinson’s becomes clearer, each pathway proving additional targets for intervention to ease the symptoms of disease, and to halt progression — in effect, to provide a cure.
Defining a Gene Mutation
You may notice gene variants/mutations have long names. This is because they are very specific. As Dr. Farrer said, “Genetics pinpoints the precise nucleotide change of the 3 billion pairs (actually six billion, three billion from mom; three billion from dad) we inherit.”
Let's break down SNCA, c.209G>A (A53T)
SNCA: tells us the specific gene name or locus
c.: stands for the 'coding' sequence
209: tells us the mutation's exact location
G: tells us which nucleotide is mutated, in this case guanine
A: tells us what the last nucleotide is mutated into, in this case adenine
(A53T): the amino acid that is in turn affected by this mutation, in this case the 'A' alanine at position 53 of the protein is substituted for a 'T' threonine
Dr. Farrer is Canada Excellence Research Chair in Neurogenetics and Translational Neuroscience at the University of British Columbia. He received PDF support in 2004 and 2011. Visit his website at www.can.ubc.ca.