The Zhang lab will explore how misfolded proteins form aggregates in cells, and identify small molecules that prevent this harmful accumulation. To function properly, most proteins associate with other proteins. In some cases, these clusters can form their own transient “compartments” within the cell. When cells are subjected to a stress such as chemotherapy, for example, some RNAs and proteins coalesce into compartments called stress granules. What isn’t clear is whether these stress granules accelerate—or deter—the formation of toxic aggregates of misfolded proteins. Using a novel technology that we developed for monitoring the formation of misfolded or aggregated proteins in live cells, our lab has determined that at least one type of protein is folded properly when it is recruited into stress granules. Now, combining this innovative technique with cutting-edge tools in synthetic chemistry, biochemistry, and cell biology, we will determine whether the same is true for other proteins commonly found in these compartments. Then, by disrupting the process, we will assess whether clustering protects these proteins from misfolding. Finally, we will develop small molecules that can stabilize the formation of intracellular compartments and test whether these molecules can prevent lethal protein aggregation in both cultured cells and fruit flies. This work could lead to novel therapies for neurodegenerative disorders that involve protein aggregation.