Everyone in the Parkinson's disease (PD) community likely has heard this question and asked it themselves. We say that PD is rarely caused by genetics, but what does that mean for those living with the disease today, their children and family?
There remain many more questions surrounding the genetics of PD than answers, but researchers have promising leads and good ideas of how to learn more. Scientists have identified two causal genes associated with Parkinson's, but -- important to note -- not all individuals with mutations in those genes will develop the disease. Researchers know of a handful of risk genes, too, which could interplay with other factors to lead to Parkinson's. The Michael J. Fox Foundation is driving research efforts to learn more about Parkinson's genetics and to speed the process of translating these findings into better treatments and a cure.
Translating Genetic Discoveries into Therapeutics
"Focusing on PD patients and those at risk for PD with genetic mutations will allow us to track the disease process at the earliest stages of illness," says Ken Marek, MD, principal investigator of the Parkinson's Progression Markers Initiative (PPMI). "This population will teach us about the biology of Parkinson's disease and will accelerate our research toward a PD biomarker and more effective PD therapies."
As recently as the late 1990s, scientists thought there was no genetic component to Parkinson's. However, through the study of one family with a high incidence of PD, in 1997 researchers discovered a genetic mutation that can cause the disease. While this mutation, in the SNCA gene, is incredibly rare, it led scientists to the hallmark pathology of PD. Researchers studied the SNCA gene and found that the protein it encodes, alpha-synuclein, clumps in the cells of all PD patients.
In 2004 Parkinson's researchers discovered the LRRK2 gene mutation, the greatest known genetic contributor to PD, which still accounts for only one to two percent of all PD cases. In some ethnic populations (e.g. Ashkenazi Jewish), more cases of PD are attributed to the LRRK2 mutation, but researchers not yet know why. A mutation in the LRRK2 gene heightens activity of the LRRK2 kinase, which has become a major focus of drug development.
Investigators are pursuing, too, the risk genes they have identified thus far: GBA, Parkin, PINK1, DJ-1. Much like how the SNCA mutation pointed to alpha-synuclein clumping, scientists hope to follow these genes to proteins and pathways that may be involved in idiopathic PD, too.
In addition, researchers are looking for more genes associated with PD by profiling the risk with a causal gene like LRRK2. We know that not everyone with this mutation gets Parkinson's. Could other genetic variants lead some people to develop PD? Are there protective factors that keep some people with the mutation from symptom onset? Such increased risk or protective factors could be seen in idiopathic PD patients, and lead scientists to new targets for treatments.
Contributing to Drug Development
These genetic findings have opened the door to a whole new avenue of PD research. While knowledge of Parkinson's mutations points to potential drug targets that will speed disease-modifying therapies, it does raise questions about the likelihood of PD among family. And, right now, knowing one's genetic makeup does not change the course of treatment.
However, those who know they have a genetic mutation associated with Parkinson's have a valuable role to play in research. They have the power to change the status quo. As it's been stated, investigators can learn a lot by studying the biology of people with a PD mutation, and what they learn can translate to drug development to benefit all people living with PD.
PPMI, a landmark study sponsored by the Foundation, launched a genetics arm in February recruiting individuals with a LRRK2 or SNCA mutation -- people with and at risk for Parkinson's. The study will collect data and biological samples over five years to look for PD pathology. Learn more about the PPMI focus on genetics.†
We have much to learn, but looking back to that first SNCA mutation discovery, it is remarkable what we know now compared to 15 years ago. Furthermore, the Foundation is calling on the PPMI infrastructure, emerging technologies and a growing list of PD-related genes to hasten the pace.
For most families with Parkinson's, the heritability of the disease is extremely low. But those families with a higher inherited risk can help us solve for the unknowns around the genetics and likelihood of PD and lead us to answer the ultimate question: What is the cure?
This piece first ran in The Fox Focus on Parkinson's Spring 2014 newsletter. Read more.