Genetics Has Revolutionized Parkinson’s Research. So What?
I was at a scientific meeting recently talking about neurological diseases in general and it struck me that every single speaker used human genetic data as an example of a cause of disease. This wasn’t true when I started out in research - we simply didn’t have the information at that time. Now we have a lot of information supporting that genetics can play a role in whether you get a given neurological disease during your lifetime. And we all inherently understand genetics - we all at least have parents that we inherited about half of our genes from and we understand how features ‘run in families’. So that genetics contribute to disease risk, as we put it in genetics language, should be intuitive - and it should be useful in thinking about how to treat diseases.
Where things get complicated is that the amount that genetics contribute to disease varies depending on which set of people we are looking at. To use Parkinson’s disease (PD) as an example, we can find families where we see about half of the people in each generation are affected mas o menos (to use my rudimentary Spanish as WPC will be in Barcelona), or a dominantly inherited disease. However, most people with PD don’t have a strong family history but when we look at very large numbers of people compared to those that don’t have disease we see lots of individual genetic variants that add up together to explain about one third of the disease risk over lifetime. What makes PD special is that these two sets of people (so-called familial vs. sporadic cases) can be linked because they are actually different types of variation in the same genes. In turn this means that the distinction between inherited or not is a matter of degree, and it is important to note that other factors like aging also play a role in the disease so genetics isn’t everything - it’s just something that is relatively easy to document.
Some of the people I know with PD dislike being referred to as “patients” because patience isn’t helpful when living with a neurological condition. The ‘so what’ about genetics is that while it has explanatory power, by itself identifying a gene isn’t as useful as turning it into a therapy. Most of the time, we scientists have to be humble and acknowledge that gene discovery is a first step, there is a long road to turning that into something that looks like a drug for a disease. However, in PD we have made some early progress in this direction in that at least one of the genetic drivers of disease, a gene called Leucine-rich repeat kinase 2 (LRRK2) is under investigation in clinical trials as a disease slowing agent in PD. We don’t at this time know that drugs targeting this gene are going to be effective as at the time I’m writing this the results of the trials have not been reported but this example (and there are many others) shows that at least in some cases there is the opportunity to move basic discoveries into the clinic.
The reason I mention LRRK2 is because (1) it’s been our major research focus since 2004 and I’m a bit obsessive like that and (2) it’s a great example of the information we can pull out of the complex genetics of PD. Broadly, there are two types of genetic change in LRRK2 that affect PD risk; either there is genetic variation that changes the sequence of the LRRK2 protein or there is variation that changes how the gene is expressed. The former ‘coding’ variation is found in families with disease (again mas o menos, there is some subtlety but I’ll skip the more arcane issues) and the latter ‘non-coding’ variation is associated with sporadic PD. In the last couple of years we have used both types of genetic variants to show how LRRK2 works in specific cells in the brain, mainly a cell type called microglia that play important roles in inflammation, something that has been associated with PD for many years. But the key is that these apparently different types of genetic changes, coding or non-coding, point in the same direction - that too much of a good thing (here the activity of LRRK2 in inflammation) is bad for you.
And that, really, is the point of the work we do, which is to take a complex problem like the genetic basis of PD and break it down until we have some clear insights that we can take action about. Again, we don’t know what will happen in clinical trials - when we move out of the laboratory environment and into the real world everything is messier and less predictable. I’ve heard it said that a clinical trial is a lousy way to test a hypothesis. But what this single illustration shows is that there is a process that’s worth pursuing - and something to keep pursuing for other drug targets in PD and more broadly in age-related neurodegenerative disease.
Mark R Cookson, PhD is a Senior Investigator, Laboratory of Neurogenetics, National Institute on Aging. He will be presenting at the WPC 2023 in Barcelona on the subject of “Using iPSC to address non-neuronal cells in PD” View the Scientific Program here. Twitter: @MarkRCookson1
Ideas and opinions expressed in this post reflect that of the author(s) solely. They do not necessarily reflect the opinions or positions of the World Parkinson Coalition®