To mark Parkinson’s Awareness Month, we are taking a look at how our genetics — the instructions written in our DNA — impact Parkinson’s disease risk.
First thing’s first. What are genes and why are they important?
Genes are discrete sections of DNA, the spiraling molecule that encompasses all of the information necessary to make a person. Much like individual recipes in a cookbook, each gene contains directions for building a specific protein, the body’s workforce. When the instructions in genes become scrambled, proteins either are assembled incorrectly, or too many or too few are made. In any of these cases, the proteins aren’t able to do their jobs properly, causing vital systems to break down.
Genetics contribute to, but aren’t the only factor, in Parkinson’s disease
The majority of Parkinson’s cases — more than 90 percent — are sporadic, meaning that we don’t know exactly what gives rise to the disease. Growing evidence suggests that it is caused by a combination of factors that vary from person to person, including genetics, shifts in how our genetics are regulated (a set of processes called epigenetics) and environmental exposures. These changes slowly accumulate until they reach a critical point, eventually tipping the scale toward Parkinson’s.
What about the other 10 percent of cases?
A subset of cases is considered to be genetic or “familial,” meaning they are directly linked to genetic mutations passed down through families. Although rare, familial Parkinson’s can teach us a lot about genetic risk across all cases of Parkinson’s.
It is important to remember that having a mutation in a Parkinson’s-related gene does not necessarily mean that a person will develop the disease (although their risk may be higher). As we learn more about Parkinson’s and the role genetic factors play, it is becoming increasingly clear that a complex and varied set of influences impact the chances of Parkinson’s onset.
To date, scientists have identified a host of genes that impact risk for Parkinson’s.
Some of the best known include:
LRRK2: LRRK2 mutations are found in an estimated 2 percent of all people with Parkinson’s and, in people with familial Parkinson’s, a single mutation to LRRK2 is found in 3 to 7 percent of cases. To date, more than 100 LRRK2 mutations have been found in families with a history of late-onset Parkinson’s.
GBA: The GBA gene is an important regulator of cellular waste removal systems. Problems with GBA can cause these systems to break down, allowing molecular debris to build up and damage cells. It is one of the most frequently mutated genes across the Parkinson’s spectrum, including sporadic and familial cases.
SNCA: SNCA contains instructions for the protein alpha-synuclein, abnormal forms of which comprise Lewy bodies, one of the hallmarks of Parkinson’s. These masses of sticky alpha-synuclein proteins are found throughout the brains of people with the disease and, recently, have been found in the digestive system, suggesting a possible brain-gut link for disease onset and progression. Rare DNA changes in SNCA can cause Parkinson’s, while more common changes can modify the risk for a person to develop the disease.
PRKN: PRKN is one of the biggest genes in humans. The protein for which it codes is called parkin, which supports waste removal in cells by marking debris with chemical tags. These tags are recognized by special cellular waste collectors and are disposed of. To date, more than 200 mutations to PRKN have been linked to Parkinson’s disease.
Scientists are sleuthing out SNPs to determine risk
Single-nucleotide polymorphisms, more often called SNPs (and pronounced “snips”), are tiny variations in DNA. They occur when one of the four nucleotides that make up the “rungs” in DNA’s ladder change. SNPs are easily the most common type of genetic variation (each person has 4 to 5 million SNPs scattered throughout their DNA).
Frequently, SNPs show up in areas of DNA between genes. This is important because they can act as guideposts that help scientists find genes that may be associated with disease. When they occur within a gene, they can affect a gene’s ability to produce protein and play a more direct role in disease.
While many SNPs have no known effect, others can be massively important — they can predispose people to certain conditions, impact how susceptible someone is to something in the environment like an allergen or toxin, or serve as a way to track diseases that are passed down through families.
That’s why scientists, including investigators here at the Institute, are combing the genetic code for SNPs that may be linked to Parkinson’s risk or that give rise to different presentations of the disease.
Understanding the genetic factors that influence Parkinson’s disease onset is incredibly important for determining risk and for developing treatments that slow or stop disease progression — something not possible with current therapies. Scientists at the Institute are deeply committed to unraveling this complex web of influences and to finding innovative new ways to treat the disease and improve quality of life for people with Parkinson’s.
To learn more about Parkinson’s research at the Institute, please visit vai.org/parkinsons-disease. This year’s Grand Challenges in Parkinson’s Disease symposium and parallel Rallying to the Challenge meeting for people with Parkinson’s, advocates and care partners will be held Aug. 21–22. This year’s theme is Understanding Genetic Risk. Get all of the details at grandchallengesinpd.org.