Dynamic RNA-Protein Assemblies and Neurological Disease

PROJECT SUMMARY Biomolecular condensates such as ribonucleoprotein (RNP) granules play a pivotal role in governing various aspects of RNA metabolism. Diverse genetic mutations converge on the process of biomolecular condensation, causing a spectrum of neurodegenerative diseases that includes amyotrophic lateral sclerosis, frontotemporal dementia, and inclusion body myopathy. Over the past decade, our lab has been at the forefront of illuminating the molecular basis for these diseases, including identifying novel disease genes, elucidating the normal function of these and other disease-related genes, and determining the biophysical, molecular, and cellular consequences of disease-causing mutations. These investigations have generated comprehensive insights into the regulatory mechanisms orchestrating condensation, particularly within stress granules, a type of RNP granule. Moreover, our studies have elucidated higher-order regulatory mechanisms governing condensation beyond stress granules. However, challenging questions remain regarding the physiological functions of biomolecular condensates, how condensates establish distinct identities despite sharing common constituents and principles of assembly, and how the dysfunction of biomolecular condensates is related to the pathogenesis of neurological disease. We have developed a comprehensive research program that, over the next 8 years, will address these remaining challenging questions. These include rigorous testing of the network-encoded percolation threshold hypothesis, which has the promise of providing a blueprint for understanding how cells regulate condensation as well as how we may be able to exogenously manipulate condensation for experimental or therapeutic purposes. Our research program also encompasses the investigation of regulatory factors governing the process of biomolecular condensation and decondensation. Finally, we aim to delineate the mechanisms whereby condensate dysfunction contributes to neurological diseases. Collectively, our research program will provide a comprehensive understanding of the dynamics of biomolecular condensation and the relevance of these assemblies to health and disease.