Beth Israel Deaconess Medical Center

Nov 15, 2023

Findings could open the door to potential disease-modifying treatment for patients with Parkinson’s disease Beth Israel Deaconess Medical Center BOSTON – In a study published in  Nature Communications , investigators at Beth Israel Deaconess Medical Center (BIDMC) shed new light on key cellular processes involved in the progression of Parkinson’s disease (PD). Affecting around 10 million people worldwide, Parkinson's disease is a neurodegenerative disorder caused by the progressive loss of the group of brain cells responsible for producing dopamine, a neurotransmitter that plays a critical role in regulating movement and coordination. As these neurons degenerate and dopamine levels decrease, individuals with Parkinson's disease experience a wide range of symptoms, including tremors, stiffness and difficulties with balance and coordination. Researchers in the lab of senior author David K. Simon, MD, PhD, director of the Parkinson’s Disease & Movement Disorders Center at BIDMC, in collaboration with colleagues at the University of Cambridge and Mission Therapeutics, performed complementary experiments showing that inhibiting a specific enzyme in a mouse model protects the dopamine-producing neurons that are normally lost as PD progresses, effectively halting the progression of the disease. The findings open the door to the development of novel therapeutics targeting the enzyme that may slow or prevent the progression of Parkinson's disease in people—a major unmet need. “Our lab is focused on working out the origins of Parkinson's disease and it is our hope that--one day--we will be able to slow down or even prevent disease progression in patients,” said first author Tracy-Shi Zhang Fang, PhD, an instructor in Simon’s lab. “The current study's findings pave the way toward that future.” Evidence suggests the dopamine-producing cells die off in Parkinson’s disease because something has gone awry with the clearance of the cells’ old and dysfunctional mitochondria—organelles that are the source of cells’ energy, sometimes called the powerhouse of the cell. Simon and colleagues focused on an enzyme called USP30 which plays a role in this process. In a mouse model engineered to lack the gene that produces the enzyme — known as a “knockout model” because one specific gene has been deleted for the purposes of experimentation—the researchers observed that the loss of USP30 protected against the development of Parkinson’s-like motor symptoms, increased clearance of damaged mitochondria in neurons, and protected against the loss of dopamine-producing neurons. In a second set of experiments, the team validated the knockout studies using a proprietary molecule developed by Mission Therapeutics to block the enzyme’s action in the dopamine-producing neurons. As in the knockout mice, inhibiting the enzyme’s action increased clearance of dysfunctional mitochondria and protected dopamine-producing neurons. “The two experimental strategies together are much more convincing than either alone,” said Simon, who is also a professor of neurology at Harvard Medical School. “Together, our very significant findings support the idea that reducing USP30 warrants further testing for its potentially disease-modifying effects in PD.” Co-authors included Simona C. Eleuteri of BIDMC; Yu Sun and Gabriel Balmus of UK Dementia Research Institute at the University of Cambridge and Department of Clinical Neurosciences, University of Cambridge, Cambridge Biomedical Campus; Andrew C. Pearce, Mark Kemp, Christopher A. Luckhurst, Rachel Williams, Ross Mills, Sarah Almond, Laura Burzynski, Nóra M. Márkus, Stephen P. Jackson and Paul W. Thompson of Mission Therapeutics Ltd.; Christopher J. Lelliott, Natasha A. Karp and David J. Adams of Wellcome Sanger Institute; Jin-Feng Zhao and Ian G. Ganley of MRC Protein Phosphorylation and Ubiquitylation Unit, University of Dundee. The work was funded by the National Institute of Neurological Disorders and Stroke (grant R21NS109408); the Weston Brain Institute; the Owens Family Foundation; the UK Dementia Research Institute, that receives contributions from UK DRI Ltd, the UK MRC, the Alzheimer’s Society, and Alzheimer’s Research UK as well as a grant from the Romanian Ministry of Research, Innovation and Digitization (no. PNRR-IIIC9-2022-I8-66; contract 760114); a grant from the Medical Research Council, UK (MC_UU_00018/2); Cancer Research UK (Discovery grant DRCPGM \100005); ERC Synergy grant DDREAMM (855741); CRUK program grant C6/A11224, C6/ A18796; Wellcome Investigator Award (206388/Z/17/Z); Cancer Research UK (C6946/ A24843); Wellcome (WT203144). The Sanger Mouse Genetics Project was supported by the Wellcome Trust (098051). Simon and Fang declare no competing interests. For a complete list of disclosures,  please visit the paper . About Beth Israel Deaconess Medical Center Beth Israel Deaconess Medical Center is a leading academic medical center, where extraordinary care is supported by high-quality education and research. BIDMC is a teaching affiliate of Harvard Medical School, and consistently ranks as a national leader among independent hospitals in National Institutes of Health funding. BIDMC is the official hospital of the Boston Red Sox. Beth Israel Deaconess Medical Center is a part of Beth Israel Lahey Health, a health care system that brings together academic medical centers and teaching hospitals, community and specialty hospitals, more than 4,800 physicians and 38,000 employees in a shared mission to expand access to great care and advance the science and practice of medicine through groundbreaking research and education. Journal