Project Summary Protein and RNA homeostasis are two major themes in the study of neurodegenerative diseases, as exemplified by the implications of many RNA-binding proteins (RBPs) in amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and other neurodegenerative conditions. As a major pathology in ALS/FTD, protein misfolding and aggregation, including those initiated by RBPs, manifest as a common thread among many neurodegenerative diseases. Additionally, a large collection of genetic, biochemical, and pathological evidence underscores the importance of RBPs in ALS/FTD and other neurodegenerative disease and calls for a better understanding of the functions of these RBPs and their associated cellular processes. A prominent feature of RBPs is their involvement in the formation of ribonucleoprotein (RNP) granules, including stress granules that are formed by a variety of RNAs and proteins under stress conditions. Stress-induced RNP granules are considered to play important roles as part of normal stress responses in the cell and in the pathological cascades underlying a range of human diseases including neurodegeneration. However, the molecular basis of RNP granule formation and the full spectrum of RBP functions remain to be elucidated. The goal of the proposed project is to investigate the molecular mechanism of protein and RNA homeostasis related to stress-induced RNP granules and disease-associated RBPs. The specific aims include understanding the diversity and functions of stress-induced granules in physiological and disease-relevant conditions, elucidate the mechanism of context-dependent granule assembly, and uncover novel functions of disease- associated RBPs such as TIA1. We propose a series of fundamental studies that combine biochemical, molecular, and genetic approaches and usage of state-of-art cellular and animal models to shed light on the novel structures and pathways related to protein and RNA homeostasis and ALS/FTD pathogenesis. Successful completion of the project is expected to provide insights into fundamental mechanisms of neurodegeneration in ALS/FTD that may ultimately lead to development of novel interventions to treat ALS/FTD and other relevant neurodegenerative diseases.