Everything you need to know about Parkinson disease genetics: An interview with an expert
Heredity
I am the family face;
Flesh perishes, I live on,
Projecting trait and trace
Through time to times anon,
And leaping from place to place
Over oblivion.
The years-heired feature that can
In curve and voice and eye
Despise the human span
Of durance – that is I;
The eternal thing in man
That heeds no call to die.
Thomas Hardy
Who is Mathew Farrer?
Mathew Farrer is one of the premier scientists who has been engaged in unlocking the genetic mysteries of Parkinson’s disease. He works at the University of Florida Fixel Institute for Neurological Diseases and the McKnight Brain Institute. We had the privilege of sitting down with him and picking his brain about the current state Parkinson’s genetics and where the field is going.
1) So what is the genetic code, what are genes, why are they important?
Each living organism on the planet has a genetic “blueprint” of DNA comprised of an enormous string of four nucleotides or letters called A, G, C and T, in what appears to be a random order e.g. AAACCGAACGGC etc. Much of that sequence is similar between organisms, which tells us that all life originated from a common ancestor, but much is also different— and influences whether that organism will be a plant, a worm, a mouse or a human being. Genes are specific regions of that sequence, typically about 1-2% of the DNA overall, that are transcribed and then translated into proteins; in these regions the sequence of letters is not random. In genes, and specifically in exons, sets of three adjacent nucleotides (or codons) encode amino acids e.g. AAA encodes lysine, CCG encodes proline, AAC encodes asparagine etc. These amino acids will be joined together to make a protein. In humans there are about 22,000 genes encoding several hundred thousand proteins. And in human populations there is also a lot of common genetic variability, more than ~7,000,000 subtle changes in ~3,000,000,000 nucleotides, which may be different between one unrelated person and the next. Those differences make us unique individuals. However, in families, the DNA sequence is passed down from one generation to the next, half the code from Mum, half from Dad, and shuffled a little, like a deck of cards, in that process. That’s why family members often look alike …the family face….and may even act alike too.
2) What do you mean you’re a ‘gene hunter’?
My work tries to identify the genes and the genetic variability within them that is responsible for differences between specific individuals— within a family or within a population. The genetic differences which interest me the most are why some people develop Parkinson’s disease, while other members of their family, or within that same population do not? I started this work twenty-three years ago, before any genes for Parkinson’s disease had been found. With 3,000.000,000 nucleotides to sift through and check— it was a daunting task to compare the genome sequence of one person with disease— to a person without. One of the genes I found is known as ‘leucine-rich repeat kinase 2’ or Lrrk2 (said ‘lark 2’) and a specific change of a ‘G’ to an ‘A’, at position 6,055 of the coding sequence and on chromosome 12 at position 40,340,400. Normally the amino acid encoded here is a glycine at position 2,019 of the protein, and that single nucleotide mutation causes that amino acid to become a serine. The consequence of this single letter mutation is generally Parkinson’s disease.
3) How often do such mutations happen?
Chr12: 40,340,400G>A (LRRK2 c.6055G>A, p.G2019S) …in genetic shorthand …may appear sporadically in a population or may be found in families in which many relatives are also affected. In North America/Europe the frequency of this change is ~0.0004 or 1/2,500 people but generally Parkinson’s disease only manifests later in life and in about one third of cases. Why isn’t everyone affected equally? We do not know all the factors but in some people there are additional genetic changes that compensate and mask their symptoms— that influence their age of onset and perhaps beyond their life expectancy. There are also environmental factors such as smoking that also lessen the likelihood of becoming affected with Parkinson’s disease (though the risk of lung cancer in smokers is greater!). Curiously, almost all people with Chr12: 40,340,400G>A (LRRK2 c.6055G>A, p.G2019S) inherited their mutation from a single common ancestor, who lived about ~3,000 years ago. They are almost all very distant cousins! We think the mutation originated in the Berber people of Northern Africa and ‘travelled’ around the world with these ancient seafaring peoples— and it made its way through the people they traded with— although that’s a tale for another blog. However, there are now about 200 other genes implicated in Parkinson’s disease, and many specific genetic changes within them. These genetic variants may be more or less frequent in the population with as great or generally more modest effects on risk..
4) How can a single letter change cause Parkinson’s disease?
This is what we have to figure out! We know for certain this specific mutation absolutely causes Parkinson’s disease, and that knowledge combined with genetic engineering and neuroscience give us the tools, the ‘precise’ models, to investigate. After ~15 years of intense study, and by many research teams, we believe we are coming to a consensus on how LRRK2 p.G2019S causes molecular, cellular and neuronal dysfunction. LRRK2 is a ‘kinase’ a special type of protein known as an enzyme, that catalyzes a chemical reaction, adding a phosphate group (-PO4) to a specific set of proteins (or substrates) to change their function. By this means, LRRK2 helps to control intracellular trafficking. Dopamine neurons in Parkinson’s disease are progressively lost in the brain, leading to motor symptoms— these cells have long skinny axons that maintain trafficking between synapses in the striatum to their cell bodies in the substantia nigra. By analogy, if this were the engine of a car, we have found the specific faulty part e.g. the cracked spring that normally maintains tension of the serpentine belt.
5) How can we fix a genetic problem?
Knowing exactly what the problem is means that we can now try to fix it. By this approach we intend to provide more than symptomatic relief, we intend to halt disease progression and potentially stop its occurrence altogether. Already a number of different drugs, using different approaches, are targeting LRRK2 and its kinase activity in human clinical trials. In well selected patients, these drugs may herald a new generation of ‘precision’ treatments likely to halt Parkinson’s disease in patients with this specific molecular problem.
6) What does this genetic information mean for my family, my children? Why should I take part in genetic research?
If you have a genetic mutation that is known to lead to Parkinson’s disease, your children have a 50% chance of inheriting that genetic variant, and may have an elevated risk of developing symptoms. However, the effects of most genetic variants remain associated with age and they are not fully penetrant. In the 20th century, Parkinson’s disease was largely considered sporadic for obvious reasons, which are just as valid today, and why genetic studies were not widely pursued. Even now, genetic heritability is only thought to explain about 27% of the variance observed in Parkinson’s disease symptoms and progression, and only a small fraction of those genetic factors have been found. Most genes and variants leading to disease remain enigmatic. Thus medical research very much needs patients to consider taking part in genetic research—in order to find the remainder. Only then, will we appreciate the molecular complexity of this disease, and will we be able to model it with any accuracy— or to fix it. Back to that car engine analogy, while we have taken a peek under the hood, we’ve yet to figure out all of the component parts, or how those actually work together to make that motor run…but innovation is rapidly accelerating genome sequencing and computation, and with the help of patients and families— with your help— we are making tremendous progress!
This blog is brought to you by Michael S. Okun and Indu Subramanian.
To read more books and articles by Michael S. Okun MD check Twitter @MichaelOkun and these websites with blogs and information on his books and http://parkinsonsecrets.com/ #Livingwith Parkinson’s #EndingPD #Parkinsonsecrets #LessonBedside and https://www.tourettetreatment.com/
He also serves as the Medical Director for the Parkinson’s Foundation.
To see more on Dr. Indu Subramanian she does live interviews of experts in Parkinson’s for the PMD Alliance.