UF-led researchers link new genetic mutation to increased risk of Parkinson’s

New research by a University of Florida-led international team has revealed evidence linking a new genetic mutation to greater risk of developing Parkinson’s disease.

portrait of matt farrer
Dr. Matthew J. Farrer

The finding of the RAB32 Ser71Arg variant, reported April 10 in The Lancet Neurology is the latest advance by UF neurogeneticist Matthew J. Farrer, Ph.D., senior author of the new paper, whose lab has made past key discoveries involving genetic mutations that can cause Parkinson’s.

The new discovery unites the biology of several major genes for Parkinson’s disease, Farrer said. This knowledge will help scientists focus studies aimed at developing new medications to slow or halt progression of the disease.

Using gene-sequencing techniques on blood samples from families with a history of Parkinson’s, the research team of 36 authors across more than a dozen major centers described the variant in 16 individual families from multiple ethnic groups.

The family members — from Tunisia, Turkey, Italy, France, Germany, Poland, Great Britain, Canada and the U.S. — appear to be distant cousins originating from a single ancestral family that has settled around the world, Farrer said.

photo of Farrer and doctor Jordan follett in Farrer's office looking over scans.
Drs. Matthew J. Farrer and Jordan Follett

“To predict and prevent Parkinson’s disease, we need to know what is really wrong at a fundamental molecular level,” said Farrer, a professor of neurology and investigator at the McKnight Brain Institute.

Parkinson’s is a progressive neurodegenerative disorder that causes tremors, stiffness, slowness and problems with balance and in later stages can affect cognition and swallowing. Genetics drive disease risk in about 10-15% of Parkinson’s cases, but of those, only up to about a third so far have been linked to specific disease-causing mutations, according to current research. Among other factors that could increase risk of Parkinson’s are head injury and exposure to chemicals such as herbicides.

In 2005, Farrer and collaborators first linked the LRRK2 Gly2019Ser mutation to Parkinson’s disease in several families in Europe and North America. This mutation causes the LRRK2 protein’s enzymatic activity to be constantly switched “on,” Farrer said. In 2011, his lab led a study implicating another gene, VPS35 Asp620NAsn, in familial Parkinson’s, and that gene also activates LRRK2. Now, Farrer and colleagues have identified yet another gene, RAB32 Ser71Arg, that likewise activates LRRK2 protein.

“It’s not a coincidence, it’s convergence,” Farrer said. “It is obvious many proteins encoded by major genes for Parkinson’s disease are involved in the same pathway, and these pathogenic variants also augment the immune response.”

Farrer and Follett review scans on a fancy microscopeFor the new study, Farrer’s team analyzed clinical and genetic data, combining resources held in private and public Parkinson’s databases with participants’ consent. Overall, the study included data on 8,847 patients and 65,693 unaffected participants. Initially, the researchers found the new variant in nine individuals within three families, and then with worldwide collaborators found 13 more patients. The team performed structural modeling of RAB32, cloned the gene and its variant to study the interactions of the protein encoded and assessed LRRK2 activity in these cellular models.

“It’s a culmination of teamwork and luck,” said Jordan Follett, Ph.D., a postdoctoral associate in Farrer’s lab and a co-author of the paper. “When you have a global team, it’s easier to accelerate the work.”

farrer and follet having a conversation in the lab

One limitation of the study, Farrer said, is the need to accurately define the mutation’s “penetrance,” or the probability of developing Parkinson’s in people who have inherited the variant. That will require far more participants, he said.

As a next step, he is working to assess worldwide frequency of RAB32 Ser71Arg to estimate when and where it first originated, in collaboration with the Global Parkinson’s Genetics Program, or GP2. In addition, Farrer said that with support from the Michael J. Fox Foundation he has designed novel mouse models to study the variant in relation to Parkinson’s and possible interventions.

Read the paper in The Lancet Neurology.

Read Dr. Farrer’s article in The Conversation.