Co - Mentor
Regulation of RNA in stress and neurodegeneration
Neurodegenerative disorders are a major public health burden, with dementias including Alzheimer’s disease alone costing ~$243 billion annually in the U.S. The discovery of new diagnosis and treatment strategies that target shared molecular mechanisms of neurodegenerative diseases could therefore have a tremendous impact on human health. Defects in proteostasis or regulated protein production, folding, and degradation, and aberrant activation of the integrated stress response (ISR) pathway are shared molecular features of a wide array of neurodegenerative diseases including Alzheimer’s disease, Parkinson’s disease and amyotrophic lateral sclerosis (ALS). Genetic perturbations in proteostasis and ISR factors cause neurodegeneration, with tissues from patients and animal models of neurodegenerative diseases exhibiting markers of an altered ISR and defects in proteostasis such as insoluble protein aggregates in neuronal cells. An understudied link between proteostasis and the ISR is the evolution of stress granules, RNA-protein assemblies that form when translation is repressed during stress, into disease-associated protein inclusion bodies. While several models have been put forth to explain how stress granules are mis-regulated in the context of neurodegenerative diseases, it is unclear mechanistically how stress granule induction, composition, material properties, and disassembly are affected by altered proteostasis. The goal of this collaborative project is to determine how proteostasis defects impact mRNA regulation and stress granule properties. We will approach this problem by applying powerful single molecule fluorescence imaging techniques to visualize mRNAs and stress granules in novel human cell culture models of neurodegeneration. This research will contribute to our understanding of the molecular mechanisms underlying neurodegenerative disease, with the potential to inspire therapeutic strategies.