Grant: Project Grant

Cells are constantly exposed to various stresses that cause deleterious damages to essential molecules, such as proteins. To deal with this, cells stop the production of proteins from RNA and store these molecules in a compartment called stress granules. Once stress is resolved, stress granules are rapidly disassembled and protein production resumes. Blocking this process promotes cell death, indicating that effective stress granule disassembly is crucial for cells to survive post-stress. In neurodegenerative diseases, Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia, stress granule proteins are frequently mutated and aggregate into rigid clumps that are toxic to cells. In this project, we are testing the hypothesis that in disease, the combination of mutations in stress granule proteins and defects in stress granule disassembly of stress granules causes protein aggregation that promotes neurodegeneration. As such, the goal of this project is to determine how stress granule disassembly is regulated normally and how defects in this process contributes to protein aggregation and neurodegeneration. We will study this problem in the cell type that degenerates in disease, called neurons, using state of the art microscopy and biochemistry methods. The majority of the neurons are made early in our development and age with us. Consequently, these cell types accumulate damages from repeated exposure to stressors. By identifying the cellular processes that deal with stress-induced damages, our goal is to develop new strategies to promote their actions and aid in treatments for neurodegeneration.