PROJECT SUMMARY A hallmark of many neurodegenerative diseases is the presence of abnormal protein aggregates in neurons of the brain and spinal cord. Two related diseases in which there has been rapid progress in understanding the origins and consequences of such protein inclusions are Frontotemporal Dementia (FTD) and Amyotrophic Lateral Sclerosis (ALS). FTD is characterized by progressive behavioral, cognitive, language and motor symptoms and an average life expectancy of 7-13 years from diagnosis. ALS first manifests as peripheral muscle weakness but progresses rapidly and is usual fatal due to respiratory failure within 2-5 years from diagnosis. It has become clear that FTD and ALS are closely related diseases with an overlapping spectrum of symptoms. In recent years, through work by us and others, dynamic ribonucleoprotein (RNP) assemblies known as stress granules (SGs) have been implicated in the formation of TDP-43 inclusions, and many ALS/FTD-causing mutations have been shown to affect SG behavior. Compelling recent studies have shown that aggregation of proteins into SGs may also be central to the etiology of tauopathies, including Alzheimer’s disease. Using models of neurodegeneration in stem-cell derived cortical neurons and in flies, the research proposed in this application is designed to fundamentally enhance our understanding of how SGs are related to mutant-dependent, and to develop and evaluate novel strategies for therapeutically targeting abnormal granules. Our ambitious study will lay the foundation for a novel paradigm to study and to potentially treat dementia and related neurodegenerative diseases.