Clemens R. Scherzer

Parkinson’s Disease: Brigham and Women’s Scientists Identify Five Genetic Loci Linked to Rapid Disease Progression Interview with:

Clemens R. ScherzerClemens R. Scherzer, M.D.
Center for Advanced Parkinson Research
Harvard Medical School
Brigham and Women’s Hospital
Boston, MA What is the background for this study?

Response: Parkinson’s disease is the fastest growing brain disorder. The number of patients is projected to double to 14 million by 2040. The total cost of Parkinson’s is $52 billion every year in the U.S. Yet, there are no medicines available to slow the disease. Current treatments temporarily alleviate symptoms, but do not address the underlying disease process, which continues to relentlessly progress.

To begin to solve this puzzle, we searched the genome of 3,821 Parkinson’s disease patients for genetic variants linked to rapid progression over time to dementia, which is a major determinant for a Parkinson’s disease patient’s quality of life. These patients were deeply characterized in the International Genetics of Parkinson Disease Progression (IGPP) Consortium, a grass-roots, collaborative network of Parkinson’s investigators, with 31,578 longitudinal study visits over up to 12 years from disease onset. What are the main findings?

Response: We found five progression loci — regions in the genome where glitches were associated with a rapid disease course. We discovered variants in the RIMS2 locus had a more than 2.5-times stronger effect on progression than GBA (a progression gene we and others previously characterized that is targeted in ongoing clinical trials for PD) and APOE4 (a major Alzheimer’s gene).

RIMS2 encodes the Regulating Synaptic Membrane Exocytosis 2 protein, a RIM family member, involved in docking and priming of presynaptic vesicles. What should readers take away from your report?

Response: Genetic drivers of disease progression should be ideal drug targets for turning fast progressors into slow progressors and thereby substantially improve patients’ lives.

The genetics of cognitive progression and susceptibility diverge in Parkinson’s disease. This raises the hypothesis that partially different mechanisms might be at play during disease onset and disease progression. Because most of what is known about the disease is about onset mechanisms, this might open up a different way to think about the disease biology and drug development. What recommendations do you have for future research as a result of this work?

Response: I think these are very exciting and promising times for medicine. We are on the verge of shifting from susceptibility genetics to prediction and progression genetics and, hopefully in the near future, precision medicines tailored to a patient’s genetic blueprint. Much more work is needed to get to this goal.

Disclosures: Brigham and Women’s Hospital holds a US provisional patent application on the polygenic hazard score for predicting PD progression. Outside this work, C.R.S. has served as consultant, scientific collaborator or on scientific advisory boards for Sanofi, Berg Health, Pfizer, and has received grants from NIH, U.S. Department of Defense, American Parkinson Disease Association, and the Michael J Fox Foundation (MJFF). 


Liu, G., Peng, J., Liao, Z. et al. Genome-wide survival study identifies a novel synaptic locus and polygenic score for cognitive progression in Parkinson’s disease. Nat Genet (2021). 



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Last Updated on May 7, 2021 by Marie Benz MD FAAD