Abstract

A common feature of many neurodegenerative diseases such as Amyotrophic Lateral Sclerosis (ALS) is the presence of abnormal protein aggregates in nerve cells in the brain and spinal cord. Recent research suggests that the formation of these protein aggregates may be linked with the way cells respond to environmental conditions. When cells are exposed to stress, they follow an “emergency response” plan, in which many cellular activities, such as synthesis of new proteins, are suspended in structures known as “stress granules”. These granules sequester essential protein and RNA molecules and the underlying molecular mechanisms are currently being studied intensively. Strikingly, many ALS-causing mutations lie exactly in the parts of the proteins that are important for stress granule assembly. Follow-up studies have shown that the formation and clearance of stress granules is often abnormal in ALS patient cells, and there is growing support for the idea that abnormal stress granule biology is closely related to the pathogenesis of many neurodegenerative diseases. Importantly, it has recently been shown that therapeutic reduction of a known stress granule protein prolonged survival in animal models of ALS. Our proposed research is designed to greatly enhance our understanding of how stress granules are related to neurodegeneration. Ultimately, we hope to identify potential novel targets and continue the development of new therapeutic approaches for ALS and other neurodegenerative diseases.