Cool demonstration that the genetic determinants of Parkinson’s susceptibility and progression are importantly different


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By Jamie Talan

June 17, 2021

Article in brief

Researchers at Harvard Medical School have found unique genetic variants that drive disease progression and could be used to determine which patients will progress to Parkinson’s disease dementia. The findings may help neurologists determine which patients have a more aggressive disease course and shine light on new potential therapy targets to decrease progression.

Research has suggested that genes that increase the risk for Parkinson’s disease (PD)—or any other neurodegenerative disease—also drive disease progression. But a new study led by researchers at Harvard Medical School has identified unique genetic variants that drive disease progression and can be used to predict which patients will progress to PD dementia.

This surprising discovery, published online on May 6 in Nature Genetics, could help neurologists identify patients who may have a more aggressive disease course and offer new treatment targets to slow progression. The finding also hints that a genetic signature could help answer the most vexing question patients ask on the heels of diagnosis: What will happen to me over time?

Nearly everything scientists know about PD genetics is about susceptibility or identifying genetic triggers that put a healthy person at risk for developing PD in the future.

“We were interested in understanding the genetics behind disease progression, and why some people develop dementia over time and others don’t,” said Clemens R. Scherzer, MD, director of the APDA Center for Advanced Parkinson Research and the Precision Neurology Program at Brigham & Women’s Hospital, and professor of neurology at Harvard Medical School.

“We wanted to do a genome-wide scan to see if we could identify variants linked to slow or more rapid progression and whether we can find genetic variants that can influence who will develop dementia. In the future, we hope to use genes like a crystal ball to predict how patients will do and to develop treatments to prevent poor outcomes from occurring. Our study is a first step towards this goal.”

Study design, findings

To conduct the research, Dr. Scherzer reached out to top scientists around the world who study PD and have large pedigrees to help answer the question of whether there are different genes that drive progression and if unique genetic markers were associated with clinical rapid progression of PD dementia. The scientists performed a genome-wide survival study (GWSS)—pulling data from 18 different cohorts from around the world—of 11.2 million variants in 3,821 PD patients over 31,053 longitudinal study visits conducted over the course of a dozen years. The median follow-up was 6.7 years.

Dr. Scherzer said they found five loci associated with PD progression and developed the first polygenic hazard score for predicting the progression of PD over time to dementia (PDD).

Three of the five loci were novel—RIMS2, a gene involved in synaptic vesicle docking, TMEM108, and WWOX. The other two—GBA and APOE4— confirmed the importance of the two genes as progression loci for PD. RIMS2 carriers had a 4.7-fold increase in the hazard ratio to progress to dementia compared with those who didn’t carry RIMS2. This gene has never been associated with PD before.

People with an APOE4 allele also had a 1.5-fold increased risk of progressing to dementia. TMEM108 knockout mice have abnormalities in dendritic spine formation, and the animals develop cognitive problems, said Dr. Scherzer. A recent genome-wide association study (GWAS) showed that WWOX is a risk locus for Alzheimer’s disease.

“It was a surprise that the GWSS progression loci diverge from GWAS susceptibility, suggesting that the genetic triggers responsible for starting the disease and the genetic drivers progressively advancing the disease might be largely different,” he added.

“Our findings suggest a new paradigm for drug development. Disease-modifying drugs that target the genetic drivers of disease progression should be prime targets for turning fast progressors into slow progressors and substantially improve patients’ quality of life.”

Expert commentary

“This is a very exciting finding,” said Pascal S. Kaeser, MD, associate professor in the department of neurobiology at Harvard Medical School. “It shows us that there are genes that increase the risk of getting PD and other genes that regulate the progression of the disease itself. Previous work on these genes allows us to put this finding into context and, hopefully, to use it to help patients with PD.”

“This study illustrates the importance of connecting basic and translational research,” added Dr. Kaeser. His lab studies the RIMS2 gene and related genes, which have been shown to control the secretion of neurotransmitters, and specifically dopamine. “The correlation with disease progression is really strong, and the field will have to figure out how RIMS2 does this and leverage the finding to help do something for patients.”

“The discrepancy in the genetic signatures for developing the disease and for disease progression has important implications for therapeutics,” added S. Pablo Sardi, PhD, the therapeutic area head in the rare and neurological disease research branch at Sanofi. “The fact that GBA, but not other genes, appears as both a risk gene for getting PD and for a worse prognosis, PD dementia, is intriguing.”

The pharmaceutical company in 2017 launched a clinical trial of a medicine targeting the GBA pathway. Mutations in GBA, the most common risk gene for PD to date, cause the aberrant build-up of proteins, including alpha-synuclein. While the phase 2 trial did not meet its primary endpoint and the trial was stopped, Dr. Sardi and his colleagues are still investigating this pathway and how to modulate its effects on PD progression.

“I applaud the team for a bold study. Looking at the genetics of disease progression is a herculean task. These novel findings confirm what we initially suspected, that susceptibility and progression are different. While we wait for independent confirmation of the findings, this study gives us a lot of new biology to study the progression of PD and to start developing novel treatment strategies.”

“It is a very well designed and large study,” added Rodolfo Savica, MD, PhD, FAAN, associate professor of neurology and consultant at the Mayo Clinic in Rochester, MN.

Dr. Savica is interested in heterogeneity in PD, and said that while the study identifies several novel loci associated with a different progression of disease, a single mutation disease model is not always applicable to PD.

“The majority of disease is polygenic, and in this case, the genes are changing the progression of the disease. PD is caused by a number of genes working together.”

“The field is very good at identifying genetic risk factors, but it is very complicated. Whenever we are considering a patient with PD, whether it is for clinical management or enrollment in a clinical trial, we need to do a better job of identifying the right patients. It is possible that in the proximate future, this information will be used in our everyday life to identify people with these characteristics to further stratify what kind of disease they have.”

Disclosures

Dr. Scherzer has served as a consultant, scientific collaborator, or on scientific advisory boards for Sanofi, Bert Health, Pfizer, and Biogen and has received grants from the NIH, US Department of Defense, American Parkinson Disease Association, and the Michael J. Fox Foundation. Dr. Sardi is a Sanofi employee and stockholder. Dr. Savica had no disclosures.

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