Grant: Operating Grant

If you ask most biomedical researchers how molecules are organized in the cell to do specific tasks they'd likely resort to the metaphor of a factory. As in the components of a factory, the molecules that do the work in cells, like robots and humans on an assembly line, are logically arranged in time and space to perform their roles in a complex process. This description has served as a helpful and meaningful metaphor for biochemical machinery. But what if you were told that sometimes molecules are organized in the cell the way that people and airplanes are organized at an airport? Recently, such molecular organizations have been discovered in cells and they may serve a number of important cellular functions and underlie neurological diseases, including Parkinson's and Huntington's diseases and ALS, among others. Molecules in the discovered structures are arranged like oil droplets in water; loosely organized and exchanging rapidly with the cell. How many such structures, called non-membrane organelles (or NMO), could exist in the cell and what are their functions? What happens if NMOs are disrupted? These are the questions we address in this proposal. The central aim of our proposal is to create a compendium of NMOs in a model of the eukaryotic cell; the bakers yeasts. Yeast is an ideal model because it shares many genes with humans, notably those that are most primordial and those become dysfunctional with age and in diseases such as cancers, and neurodegeneration. We have shown how certain types of cell regulation including gene function and spatial organization of large cell structures depend on NMOs. The compositions of NMOs are surprisingly rich in protein molecules that when mutated, are known to underlie neurodegeneration. We hope to define how these mutant proteins cause dysfunction, perhaps by disrupting the normal functions of NMOs, and what kinds of strategies could re-stabilize them.