Precision Medicine for Parkinson’s: New Yale Center for Advanced Research

Precision medicine for Parkinson’s is the focus of the new American Parkinson Disease Association (APDA)-funded Center for Advanced Research at Yale School of Medicine (YSM).

APDA is the largest grassroots association for Parkinson’s disease in the United States. It selects institutions that not only are leaders in research, but also demonstrate excellent clinical care, offer educational opportunities for trainees, and show dedication to patient outreach. The new YSM center, to be led by Clemens Scherzer, MD, Stephen and Denise Adams Professor in the departments of neurology and genetics, is one of nine APDA centers of excellence across the country. It is the only center worldwide focused on precision medicine for the neurodegenerative condition.

“Our goal is to develop the future of precision medicine for Parkinson’s disease by bringing together the entire Yale community—the physician-scientists, researchers, engineers—to work together and identify its underlying genes and mechanisms,” says Scherzer, who notes that the funding for the new center continues a long-standing relationship between Yale and APDA.

YSM is already a world leader in research on Parkinson’s disease. Scherzer is director of the Stephen & Denise Adams Center for Parkinson’s Disease Research, which is striving to revolutionize the treatment of the disease through discovering new genes, drug targets, and biomarkers, and creating tailored therapeutics. There are 37 active Parkinson’s disease-related grants held by YSM principal investigators, as well as 29 active clinical trials. The research conducted at Yale has led to 46 publications related to t condition over the past year.

Yale is also home to Aligning Science Across Parkinson’s (ASAP) teams. A global initiative, ASAP offers prestigious $9 million awards to teams internationally for unraveling the underlying causes of the disease.

These teams are led by Scherzer, Thomas Biederer, PhD, professor of neurology, David Hafler, MD, William S. and Lois Stiles Edgerly Professor of Neurology, and Pietro De Camilli, MD, John Klingenstein Professor of Neuroscience and professor of cell biology. “The new center will connect everyone around campus interested in and passionate about advancing Parkinson’s research and care,” says Scherzer.

Beyond research, the Adams Comprehensive Parkinson Disease and Movement Disorders Care Center, led by Veronica Santini, MD, associate professor of neurology, offers world-class, multidisciplinary, and personalized care. YSM is also dedicated to educating the next generation of movement disorders specialists. Sara Schaefer, MD, associate professor of neurology and a nationally recognized leader in education, directs YSM’s movement disorders fellowship and is associate program director for the neurology residency program.

The new APDA Center designation and funding will deepen YSM’s connections with APDA, allow YSM researchers to train new investigators, and enable more outreach and educational opportunities. Furthermore, it will provide seed funding to several exciting Parkinson’s disease studies that aim to uncover key steps in the development of the condition so that researchers will eventually be able to develop more precise therapeutics.

One project is a collaboration among the laboratories of Scherzer, De Camilli, and Sreeganga Chandra, PhD, professor of neurology and of neuroscience. Studies from all three groups have independently pointed to dysfunction in synaptic vesicle endocytosis as a potential root cause in a subset of patients with Parkinson’s disease. Neurons communicate with one another by releasing neurotransmitters that are encapsulated by vessels known as synaptic vesicles. After the neurotransmitters are released, the vesicle needs to be recycled so it can be used again. Endocytosis is the process that brings the used vesicle back into the cell.

The inability of nerve cells to recycle these vesicles may be a prominent disease driver, evidence from all three labs has suggested. Scherzer’s team has created a gene activity map of Parkinson’s disease and discovered several genes associated with the condition. Interestingly, these include genes which the De Camilli team identified as key players in the regeneration of synaptic vesicles during their endocytic recycling. Mutations in the genes that encode these proteins are also associated with Parkinson’s disease. Finally, Chandra’s team found that alpha-synuclein, a key protein that accumulates as Lewy bodies in the brains of Parkinson’s patients, also might play a role in this process. “Now we’re joining forces to test whether these genes associated with Parkinson’s disease work together with alpha synuclein to perturb this key mechanism [synaptic vesicle endocytosis],” says Scherzer.

The funding will also support a second project, led by Monika Sharma, PhD, instructor of neurology in the Adams Center, studying whether a receptor named beta-2 adrenergic receptor alters mitochondrial function in Parkinson’s disease. This is a key receptor for neuromodulators like noradrenaline. During the very early stages of the disease, the locus coeruleus, a group of neurons in the brainstem that produces noradrenaline, degenerates. Now, Sharma’s team will investigate whether this loss of noradrenaline perturbs mitochondria — the cellular powerplants — in the brain. If so, medications that target the beta-2 adrenergic receptor could be used for turning on mitochondria, which malfunction in Parkinson’s, in addition to reducing levels of alpha-synuclein as the Scherzer lab and others previously showed.

None of this work would have been possible without APDA’s support. “The center will be a glue that brings together all of the Parkinson’s researchers at Yale. It will help to launch junior investigators and seeds high-risk projects that otherwise wouldn’t be funded,” Scherzer says.