When I attended the World Parkinson Congress in Montreal last October, I was uplifted by the remarkable positive energy I felt from fellow attendees with PD. Many of the folks there exhibited none of the common symptoms; others were struggling, bravely and visibly, with the disease. It was from those people in the convention hall – not the information from the lectures -- that I felt most energized and hopeful.
No, we haven’t had that “penicillin moment,” as one speaker described it – a sudden and game-changing breakthrough. But, as a quick review of the Michael J. Fox Foundation website (MJFF) reveals, we’ve come a long way in the past two decades.
Two Causal Genes
First, research has identified two “causal genes” -- SNCA and LRRK2 – which, when they mutate, can cause the protein clumping that leads to PD. Mutations in these genes don’t always lead to PD. And when they do, it’s a very small percentage of cases. Still, discovering these mutations – and the role they play in the development of PD -- has given scientists new biomarkers to target.
The SNCA Gene
Until 1997, we didn’t have any evidence of a genetic-PD link. Then scientists discovered that a mutation in the SNCA gene leads to what is now considered a hallmark of PD pathology: the clumping of alpha-synuclein protein (accumulations called “lewi bodies”), which the SNCA gene encodes. This mutation, as far as we know, is extremely rare, but it provided the first glimpse of a genetic cause for the disease.
The LRRK2 Gene
In 2004, researchers discovered another mutation – this time on the LRRK2 gene – that causes PD. Johns Hopkins scientists found that LRRK2 actually functioned like a kinase – an encoder – for alpha-nuclein protein, whose clumping they knew to be a PD feature. If they could disrupt the kinase activity, disabling the protein-building mechanism, they could halt the deterioration of dopamine-creating neurons, and thus the progress of the disease.
Scientists think the LRRK2 mutation causes about two percent of all PD cases (a higher percentage among Ashkenazi Jews and other ethnic groups). Two percent may not seem like much, but the discovery gave researchers another biomarker to target in their quest for a treatment.
In a continuation of the LRRK2 story, we learned just last week that Dr. Ted Dawkins and his team at Hopkins had created a mutation in protein s5 that blocked LRRK2’s ability to properly encode alpha-synuclein. Their research showed that blocking the mutation that causes protein clumping actually protected nerve cells of humans, rats, and fruit flies. The dopamine-producing cells were thus able to continue normal operation, keeping PD at bay.
There are other genes that don’t cause PD, like SNCA and LRRK2, but seem to be involved in various ways with the development of PD. Those risk genes include GBA, Parkin, PINK1, and DJ-1. Scientists will continue focusing on these biomarker targets, hoping to learn more about their proteins and pathways, and how they play a role in the development and progress of the disease.
You Have a Suspect Mutation. Now What?
Most people with PD don’t appear to have acquired the disease genetically. And again, possessing one of these trouble-causing mutations doesn’t necessarily cause Parkinson’s. Why some people with a mutation develop PD -- while others with the same mutation don’t – remains an important unanswered question. There is still a universe of mysterious cellular activity.
If your doctor identifies a mutation on SNCA or LRKK2, what can you do about it? Is there some pro-active measure you can take to prevent – or at least delay – the onset of PD? In a word, no. At least, not yet. But – and the MJFF considers this a big issue – you can become part of ongoing PD clinical trials. Even people without these key genetic mutations can participate as control subjects.
The Parkinson’s Progression Markers Initiative (PPMI)
People with a key mutated gene, whether they have PD or not, can join the Michael J. Fox Foundation’s PPMI, a drive to ID key biomarkers still missing in the quest to develop a treatment for PD. There is now no useful detection device available to spot disease biomarkers. For the moment, only autopsy can do that job -- not a particularly helpful therapy.
Here’s how MJFF describes PPMI:
At PPMI’s 32 clinical sites in 13 countries, nearly 800 participants — everyday patients and their loved ones — are contributing invaluable data and biosamples into the most robust Parkinson’s database and specimen bank ever created. These resources are paired with a simple online system allowing researchers to access study data and samples for complementary PD research in their own labs across the globe. Because PPMI is an observational study, research volunteers do not take any experimental drug or placebo, but agree to contribute data and samples for up to five years. A $60-million study, PPMI is sponsored by The Michael J. Fox Foundation and funded by the Foundation in partnership with 15 biotech and pharmaceutical companies.PPMI Explorations
In addition to ongoing studies of blood and urine, PPMI is pursuing other techniques to identify PD biomarkers earlier and earlier -- a scientific advance that could render eventual treatments more and more effective.
- Brain Imagery: Water circulates through the brains of people with PD differently that it does through normal brains. Scientists want to find out why, hoping the answer might speed potential treatment.
- Cerebro-Spinal Fluid: We’ve known for years that a key hallmark of PD is the accumulation in the brain of alpha-synuclein protein clumps. Cerebro-spinal fluid – which “bathes” the brain – contains that alpha-synuclein protein. What we’ve learned more recently is that the levels of that protein in the spinal fluid of people with PD is lower than it is in healthy people, since that protein in PWP is building up in the brain. Might those differences in levels of this protein biomarker in spinal fluid lead scientists to earlier PD diagnoses? Only time – and a lot more research – will tell.