Investigator:
John Vaughen, PhD
Name of Institution:
The Regents of the University of California, San Francisco
Project Title:
Tracking GBA-Dependent Lipids in Neurons and Glia Across Circadian Time
Investigator Bio:
Dr. John Vaughen obtained a bachelor’s degree in biology from the University of Chicago, was a MEXT Research Scholar at Kyoto University, completed his PhD in developmental biology with Dr. Thomas Clandinin at Stanford University, and is now a Sandler Faculty Fellow at the University of California, San Francisco. He is studying how specific fats influence brain cell function across neurons and glia.
Objectives/Background:
The GBA gene encodes glucocerebrosidase, an enzyme that is active in the lysosome, the recycling center of the cell. Glucocerebrosidase breaks down a component of the cell membrane called glucocerebroside into glucose and a simple fat called ceramide. This process regulates fats or lipids in nerve cells and glia, the brain’s support cells, and mutations in GBA is a genetic risk factor for the development of Parkinson’s disease (PD). Although current scientific methods are quite good at tracking and modifying proteins, our ability to visualize and modify lipids is quite poor, which makes the downstream consequences of damaged GBA function harder to understand. The objective of this proposal is to use well-studied living brains of fruit flies, which have complex neurons and supporting glia cells, to learn how GBA loss affects lipid localization and function. We aim to demonstrate that GBA controls important changes in cell pathways that recycle and clear waste in a manner that fluctuates with the circadian rhythm, the body’s internal 24-hour clock.
Methods/Design:
We are creating new molecular sensors that can be placed in specific regions of the brain to track how GBA mutations change the way fats are made, used, and broken down. We will look at how these fat changes interact with protein clumps commonly seen in PD, including an exciting, newly found type of harmful clump that changes in amount during the day/night cycle.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Changes in GBA and other proteins can disrupt how the brain processes and manages lipids. By understanding the effects of these changes on the brain’s lipid balance, we may be able to find new treatments to restore healthy fat processing using medicines or gene-based therapies.