About the author: Hugh Johnston’s career has focused on strategic planning, business analysis, and fact-based decision making. Grateful to have learned from skilled and innovative leaders, Hugh’s efforts have focused on the fundamental long term drivers of performance and getting results. Hugh’s contributions to thought leadership have included writing for Restaurants Canada on the drivers of performance in foodservice, and providing business insights for the Association’s annual research publication. Hugh was diagnosed with Parkinson’s disease at 56. After confirming the diagnosis, Hugh set out to learn everything he could about the disease to begin developing the skills and knowledge needed to enter the next phase of his career as a Parkinson’s Advocate. Hugh is currently an administrator for the Facebook Parkinson’s Research Interest Group (PRIG) which has 2300+ members (including many prominent researchers). Hugh is also an Advisory Board member for a major teaching hospital’s four year research project in another field on proving the effectiveness of their multidiscipline “wrap-around” care model NAVIGATE across a number of health regions in Ontario..
Not all genetic causes of Parkinson's disease (PD) are inherited; some are likely associated with somatic genetic mutations. Unfortunately, we do not have a good idea of how large the impact of somatic mutation is in PD, nor do we have an effective test to identify the mosaic of somatic mutations in any given patient. It is good to see research being done in this area to be ready for when we find our first “cure” for one of the “genetic types” of PD.
A portion of PD risk is inherited through your genome. There are a number of single gene variants (monogenetic variants) that are believed to be disease causing, greatly increasing the risk of PD, including SNCA, LRRK2, GBA, PARKIN, PINK1, and DJ1. There are an even larger number of genes associated with PD that are believed to be involved in polygenic disease (disease from many genetic variants acting together).
Normal DNA testing, (using blood, cheek swabs and saliva), is used to identify if an individual patient has inherited gene mutation(s) associated with PD. The results of these genetic tests are used to give researchers, clinicians and patients a window into the different forms of the disease they are dealing with. Different “forms of PD” can have different age of onset and different patterns of clinical symptom presentation. In fact some genic forms of PD present much like PD that is idiopathic (of unknown cause).
Possible PD, But Not Guaranteed
Not all carriers of a specific gene mutation associated with PD get the disease; an individual can have one of the more common known risk factor mutations associated with PD and not get PD in their lifetime. For example:
◾Studies have shown that GBA mutations have a 30% lifetime risk by the age of 80 (Anheim et al. Neurology 2012)
◾Lifetime risk for the p.G2019S variant of the LRRK2 gene is estimated to be approximately 42% (Lee et al. Movement Dis. 2018)
◾Twin studies have found that when one twin has PD, the other may not get the disease at all, and when both twins do get PD there are cases where there is a large gap in the age of onset.
Why doesn’t everyone with a PD associated gene mutation get the disease? One hypothesis is that there is an interaction between gene variants and other factors. These other factors (PD risk factors) may include, but are not limited to, age, sex, environmental toxins, infections, comorbidities, and lifestyle decisions over a patient’s lifetime.
It is widely accepted as fact that there is more than one single genetic mutation at play in gene associated PD, and that there may be more than one of the above PD risk factors involved in each case. One group working to put the pieces together is at the National Institutes of Health (NIH) in the USA where a group led by Andrew Singleton have developed a model that is pretty good at predicting PD.
A Challenge – The Ways We Test for DNA Mutations
Not all genetic mutations are inherited from your parents; you can acquire a genetic mutation at any time in your life. These “somatic” mutations are, for the most part, not inherited. In fact somatic mutations are the type behind many types of cancer.
As a human being develops, early cells differentiate into different types of tissue that are destined to create different parts/systems in the body. Somatic mutations that occur, both during and after development, lead to groups of cells in your body that do not have the same DNA. In fact you become like a mosaic, with different bits of genetic code in different parts of your body, including your brain.
The fully formed human brain comes from cells that differentiate into a part of a developing human embryo called the ectoderm. Any gene mutation at the ectoderm stage or later in development will show up downstream but will not affect any cells that arise from the mesoderm or the endoderm.
After the ectoderm is formed there are many opportunities for gene mutations on the way to developing fully formed mature brain cells. Take dopaminergic neurons for example:
– There are many steps, after day 12 when the ectoderm forms, to turn part of the ectoderm into some 400,000 mature fully formed dopaminergic neurons in a human brain
– Dopaminergic neurons in the substantia nigra innervate the caudate nucleus, putamen, Globus palidus and the subthalamic nucleus in the brain giving rise to a massive number of synapses that can be affected
– Glial cells that interact with dopaminergic neurons may also be affected
More Than One Kind of Gene Mutation
When we think of heritable and somatic gene mutations we are drawn to think of miscoding variants of one “bit of DNA”; a single nucleotide (C,G,A, or T), with either one or two “genetic errors” (single nucleotide mutations).
There are other types of DNA mutations, however, and a number of different processes can affect DNA mutations in populations of neurons, astrocytes and oligodendrocytes, or for that matter in individual neurons.
Credit: G Evrony, PMC 2019
These mechanisms impact neurons throughout their lifetime, not just when they are in development. You do not always need cell division (mitosis) to create a gene mutation in a single cell.
Genetic risk for PD then is more than what you inherit from your parents. How much risk? Well researchers are working on learning more about the extent of somatic mutation in many gene associated conditions including PD; “these are early days”.
How to Find a Somatic Mutation
DNA tests generally use samples from blood, cheek swaps and saliva. None of these sources of DNA information come from the cells that gave rise your nervous system. A somatic mutation that occurs after the ectoderm forms will not show up in these types of DNA tests.
One of the big challenges for researchers is that it is not easy to work out the rate of somatic mutations in a human brain. Researchers cannot easily get at a sample of the neurons needed to find somatic DNA mutations in living patients.
Using donated brains to compare DNA in different areas of the brain, and extrapolating from somatic mutation rates in other types of tissue, can help scientists estimate the size of somatic mutation risk in a given population. Unfortunately, these methods will not give a clinician a view to the specific somatic mutations in any single PD patient.
How Strong is a Somatic Mutation
Can somatic genetic mutations associated with PD have less impact on an individual than inherited ones? We do not know, but, a later age of onset, a milder form of the disease, or indeed no disease at all, might well arise when not all of a group of neurons are affected by a mutation that occurs during development.
Can a somatic genetic mutation associated with PD have a disease effect if it does not initially impact a large number of brain cells involved in movement? We do not know the answer to this question either. The brain is extremely complex; and disease effects in the brain are not linear. It might only take a critical mass of affected cells to give rise to a systemic and progressive condition like PD.
In the end, a PD patient could have any number of combined risks for PD. Having single or multiple inherited genetic risk factors for PD, combined with added PD risk from somatic mutations, and the varying effects due to the number of cells that are affected by any given somatic mutation, should lead to a wide variety of risk. Combine that with non-genetic PD risk factors and you get a formula for different types and presentations of the disease.
There have been great advances in knowledge of PD and the mechanisms involved in monogenetic risk forms of the disease. There is a good chance we will see a disease modifying treatment in the future based on discrete cellular/molecular mechanism PD subtypes, identified through a focus on a “single target” genetic variant.
Some patients will have an inherited form of a single PD genetic risk variant and some may have a somatic form as the driving force contributing to their PD.
“Indeed a somatic mutation in the brain can go undetected in regular blood DNA tests” says Ziv Gan-Or at the Neuro in Montreal. “There are several groups working on somatic mutations in PD but with very little results so far (as we need many brains and they are hard to get). So the 20-30% (heritable risk) does not include somatic mutations and therefore the real number can be much higher”
One group has reported discovering somatic copy number variants of the SNCA gene in a number of PD patients and controls. Their work found the level of somatic mutation in brains tested correlated modestly with younger age of onset. “We are pursuing somatic mutations in additional cases and brain regions, and investigating correlations between somatic mutations and alpha synuclein aggregation” says Christos Proukakis at UCL in London, UK.
We will need a way to identify the potentially important forms of somatic mutations in PD if we are to get a new “genetic variant based treatment” to “most if not all” of the patients who need it. Alas, giving a new treatment to everyone is not going to be a cost effective strategy to capturing those patients you do not have a DNA test for.
Not all genetic causes of PD are inherited; some may be associated with somatic mutations. Mutation risk is amplified by the fact that (1) there are a lot of steps in neurogenesis where mutation can occur at varying rates, (2) there are a number of types of genetic variations in PD, and (3) mutation can happen even in neurons that do not divide.
We do not yet have a good idea of how large the impact of somatic mutation is in PD, nor do we have an effective test to identify the mosaic of DNA in any given patient. What we can expect is the reach of genetic association in PD is higher than the 27% estimated for heritable PD; how high we do not know.
It is good to see research being done in this area. With a bit of luck and a lot of hard work we will be ready to meet the challenge of somatic mutations when we have our first “cure” for one of the “genetic types” of PD. And with a bit of luck and hard work we will also solve the mitochondrial DNA risk in PD, but that topic is for another article.