Regulation of lysosome positioning and function by the unfolded protein response

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Project Summary/Abstract The broad goals of this research proposal are to understand how cells mitigate the aggregation of proteins that underlie neurodegenerative diseases, and how these mechanisms are influenced by stress pathways and organelle trafficking. There are no cures for Huntington’s, Parkinson’s, and Alzheimer’s diseases, so exploring new mechanisms for how cells respond to protein aggregation is important for offering new therapeutic approaches. The first goal of this proposal is to understand how cells degrade the disease-causing form of the Huntington protein, in particular as it misfolds but before it forms the large aggregates that are found in the brains of patients. These intermediate, oligomeric forms of the Huntington protein are thought to be the most toxic, yet we do not know the mechanisms through which cells most effectively degrade them. Guided by preliminary data, we will explore how cells employ late endosome-mediated microautophagy in this degradation. Microautophagy is not well- understood at a mechanistic level, especially in mammalian cells, and this proposal is also designed to provide more general insights and tools to study this fundamental cellular process. The second overall goal of this proposal is to understand the relationships between protein aggregation, stress in the endoplasmic reticulum (ER), and organelle trafficking/positioning. Many neurodegenerative diseases induce ER stress, yet the complicated interplay between ER stress response pathways and neurodegeneration is not well-understood enough to provide a clear path for manipulating these stress pathways therapeutically. This proposal seeks to understand how a particular aspect of the ER stress response, involving the degradation of a specific mRNA and subsequent repositioning of late endosomes and lysosomes, affects the degradation and aggregation of the Huntington protein. Investigating this stress response will also help us to understand how cells maintain homeostasis in the ER, which is important in many human diseases including cancer and diabetes.