Parkinson's disease (PD) is the second most common neurodegenerative disease after Alzheimer's, affecting more than 10 million people worldwide. PD is characterized by a decrease in a brain chemical called dopamine and the death of neurons in a part of the brain known as the substantia nigra. The loss of these neurons leads to the characteristic Parkinson's tremor as well as other debilitating movement symptoms and problems with cognition, mood, and sleep.
But PD does not only involve the brain. Indeed, researchers have recently started to investigate how the function of the gut can play a role in the disease, based on long-standing data that shows gastrointestinal dysfunction in PD. Now, several researchers from Caltech have teamed up to study the neural circuitry connecting the gut and the brain, to understand how this circuitry is impacted by PD and how it may provide new targets for treatments.
The team—which includes long-time collaborators on PD research Viviana Gradinaru (BS '05), professor of neuroscience and biological engineering and director of the Center for Molecular and Cellular Neuroscience, and Sarkis Mazmanian, Luis B. and Nelly Soux Professor of Microbiology; as well as David Van Valen (PhD '11), assistant professor of biology and biological engineering and Heritage Medical Research Institute Investigator, among others—has now received a major grant from the Aligning Science Across Parkinson's (ASAP) initiative that provides more than $11 million to carry out this research.
The team proposes that environmental and genetic factors impact the connections between neurons in the gastrointestinal nervous system, which can increase susceptibility to PD triggers. These triggers include a-synuclein, a protein that, when aggregated in clumps, is toxic to cells and can trigger both PD symptoms and gut inflammation. The researchers will investigate if the process that originates in the gut can then propagate to the brain and cause dysfunction in neural circuits that presents as the classic PD symptoms.
With the new funding, the team will map out the gut–brain connections within rodent and other animal models and examine how perturbations of this circuitry can affect disease outcomes. Understanding the role that the gut–brain neural circuitry plays in PD will open new possibilities for treatments that could slow, halt, or even reverse symptoms.
The work builds on the neuroscience and neurotechnology expertise in the Gradinaru laboratory as well as the long history of gastrointestinal and PD research in the Mazmanian laboratory, and combines machine-learning and single-cell analysis techniques from the Van Valen laboratory. In addition to Gradinaru, Mazmanian, and Van Valen, the project team includes collaborators Andrew S. Fox of UC Davis, Sergiu P. Pasca of Stanford University, Ashley W. Seifert of the University of Kentucky, Roy Subhojit of UC San Diego, and Lin Tian of UC Davis.
ASAP is a coordinated research initiative to advance targeted basic research for Parkinson's disease. Its mission is to accelerate the pace of discovery and inform the path to a cure through collaboration, research-enabling resources, and data sharing. The Michael J. Fox Foundation for Parkinson's Research is ASAP's implementation partner and issued the grant.
Gradinaru, Mazmanian, and Van Valen are affiliated faculty members with Caltech's Tianqiao and Chrissy Chen Institute for Neuroscience.