Dissecting neuronal lipid metabolism

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Project Summary Dissecting neuronal lipid metabolism PI: Thomas R. Clandinin The brain is lipid rich, with the complexity of neural and glial membranes being fundamental to many aspects of neural function. To function appropriately, neural and glial membranes must maintain a cell-type appropriate composition of constituent lipids, and must continue to do so across adult life, even as ongoing vesicle fusion and retrieval make the control of lipid metabolism a fundamental challenge. At the same time, mutations that disrupt the biosynthesis and recycling of membrane lipids are associated with a large number of neurodegenerative diseases, making understanding how membrane lipids are produced, degraded, and recycled a problem of central interest. How is the lipid composition of specific cell types regulated in the adult brain, and how do alterations in lipid composition affect brain function in health and disease? This proposal focuses on the biosynthesis of glycosphingolipids, key constituents of neural and glial membranes that are evolutionarily conserved across metazoans, including humans. One of the genes involved in glycosphingolipid metabolism, Glucocerebrosidase (Gba) is associated with Parkinson’s Disease risk, as well as Gaucher Disease. However, how Gba acts in the adult brain remains incompletely understood. This proposal takes advantage of the evolutionarily conserved nature of Gba, using the fruit fly as a model to dissect the relative contributions of glia and neurons to Gba function. We focus specifically on two key questions. First, how is Gba function regulated by neural and glial activity? And second, how is Gba activity programmed during development, and transcriptionally regulated in adult neurons? These studies will broadly inform our understanding of how neural function is maintained across adult life, and dysregulated in neurodegenerative disease. As this understanding is fundamental to the development of novel drugs that modulate these pathways to prevent disease, these studies will broadly inform future therapeutic strategies.