Yale School of Medicine (YSM) teams have received three grants totaling $18 million from Aligning Science Across Parkinson’s (ASAP), a coordinated research initiative devoted to accelerating the pace of discovery and informing the path to a cure for Parkinson’s disease (PD) research. ASAP has partnered with The Michael J. Fox Foundation for Parkinson’s Research to implement the funding program.
Approximately $6 million in funding were awarded to each of three teams led by Thomas Biederer, PhD, professor of neurology; Pietro De Camilli, MD, the John Klingenstein Professor of Neuroscience and professor of cell biology; and Clemens Scherzer, MD, the Stephen and Denise Adams Professor of Neurology and Genetics, and director of the Stephen and Denise Adams Center for Parkinson's Disease Research, to advance their work.
PD is a rapidly growing neurodegenerative disorder that already affects 10 million people worldwide. The three YSM teams will search for target genes (Team Scherzer); clarify the role of lysosomes and energy supply in PD (Team De Camilli); and investigate how α-synuclein aggregates impact cognitive function in PD (Team Biederer). YSM is also home to Team Hafler, which previously received ASAP funding to investigate immune system contributions to the disease. All four teams are part of ASAP’s Collaborative Research Network (CRN), an international, multidisciplinary, and multi-institutional network of collaborating investigators who are working to address high-priority research questions.
“Thank you to Aligning Science Across Parkinson’s and The Michael J. Fox Foundation for recognizing and investing in the collaborative and multidisciplinary neuroscience research being conducted at Yale School of Medicine,” said Nancy J. Brown, MD, the Jean and David W. Wallace Dean of Yale School of Medicine. “Through exceptional team-based science, we can uncover the pathogenesis of Parkinson’s that could lead to effective therapies and a cure.”
Research projects through the lens of YSM investigators and their collaborators
“Our team’s goal is to understand cognitive impairments in Parkinson’s. Each person with this disease has their own trajectory, but many experience problems with attention and decision-making, and some progress to dementia at the late stages of the disease.
“We investigate how PD impacts the cerebral cortex, studying this brain area due to its role in cognition. The cortex is actually not commonly studied as most research focuses on motor symptoms. Specifically, we analyze how the aggregation of the pathological protein α-synuclein in vulnerable nerve cells impacts brain health.
“Our integrative approach is critical to our research, and the groups on our team are outstanding. We bring together deep expertise to track across scale changes in neuronal connectivity, network activity, and gene expression using both mouse models and human tissue.
“The goal of ASAP to advance multidisciplinary work is unique and, frankly, quite inspiring. It enables our team to understand how brain networks become vulnerable in PD over time and identify mechanisms for intervention.”
Team Biederer’s co-principal investigators are Michael Higley, MD, PhD, and Elena Gracheva, PhD, at Yale; Laura Volpicelli-Daley, PhD, at the University of Alabama at Birmingham; and Michael Henderson, PhD, at Van Andel Institute.
Through exceptional team-based science, we can uncover the pathogenesis of Parkinson’s that could lead to effective therapies and a cure.
Dean Nancy J. Brown, MD
“Human genetics studies have identified more than 20 genes whose mutations cause PD and a large number of additional variants that increase PD risk. Our goal is to advance the understanding of pathogenetic mechanisms in PD by focusing on a selected group of PD genes whose function converge on lysosomes, the organelles involved in the disposal of old/damaged material, including organelles such as mitochondria, and in the recycling of their components.
“A main working hypothesis is that defective function of lysosomes may result in their leakiness with the release of toxic components from the lysosome lumen into the cytosol, eventually leading to activation of innate immunity and inflammation. We also are exploring the importance of impaired energy metabolism in PD. Our long-term goal is to translate the information emerging from PD genetics into novel therapeutic opportunities. Understanding how mutations lead to PD requires interdisciplinary research. Specifically, we are investigating how disruptions in membrane traffic within cells of the nervous system, and the metabolic processes that support this traffic, contribute to PD pathogenesis.”
Team De Camilli includes Yale Co-Investigators Shawn Ferguson, PhD, Kallol Gupta, PhD, and Karin Reinisch, PhD, as well as Timothy Ryan, PhD, at Weill Cornell Medicine.
“Since the completion of the Human Genome Project, there has been massive progress in identifying hundreds of DNA variants as risk factors for PD in millions of patients. Why has this not led to new medicines?
“The reason is that we do not know what genes are targeted by these common glitches in patients’ DNA. Most of these glitches are in the ‘dark matter’ of the genome. They do not mutate known genes or encode proteins.
“We hypothesize that PD instead affects gene switches that turn nearby target genes on or off in specific brain cells. The goal of our study is to discover these precise target genes of PD.
“How are we tackling this problem? We are mapping a molecular atlas of millions of brain cells in Parkinson’s patients⎯termed PD5D⎯across brain space and disease progression. We use this atlas and genetic perturbations in fruit fly avatars and stem cells to pinpoint the gene targets that are switched on/off by the disease variants and that cause brain cells to malfunction.
“Why is this important? If successful, this study will precisely ID dozens of PD genes that can be used as targets for developing new precision drugs designed to slow or halt common, sporadic PD.
“Yale is one of the few institutions in the world with multiple ASAP teams. Working together, we will have incredible firepower to make interdisciplinary breakthroughs for patients⎯at Yale and globally⎯in the ASAP Collaborative Research Network.”
Team Scherzer includes Xianjun Dong, PhD, at Yale; Mel Feany, MD, PhD, at Harvard; Joshua Levin, PhD, and Ralda Nehme, at the Broad Institute; and Su-Chun Zhang, MD, PhD, at Sanford Burnham Discovery Institute.