Molecular mechanisms that match lysosome function to cellular demand

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Project Summary/Abstract Lysosomes serve as a major site for the degradation of macromolecules and play a central role in the ability of cells to sense and respond to changes in intracellular nutrient availability. Conversely, levels of intracellular nutrients such as amino acids regulate lysosomal properties, including their biogenesis, acidification, signaling functions and subcellular position. Defining the molecular machinery that allows for this coordination of lysosome function with nutrient availability is critical for unraveling how lysosome homeostasis is maintained in health and disease. This project focuses on a heterotrimeric protein complex made up of C9orf72, SMCR8 and WDR41. Our interest in this protein complex stems from our discoveries that it is recruited to lysosomes upon amino acid deprivation and is required for both degradative functions of lysosomes as well as their ability to support activation of mTORC1 in response to acute exposure to amino acids. Our proposed research thus seeks to: 1) Elucidate the mechanisms whereby cells couple the sensing of changes in amino acid availability to the recruitment of C9orf72-SMCR8-WDR41 to lysosomes. 2) Define the direct lysosomal targets of C9orf72- SMCR8-WDR41. 3) Establish how this overall pathway is integrated into the maintenance of lysosome homeostasis. While our research focuses on using human cellular models to determine the essential lysosome-related functions of this protein complex, we anticipate that our findings will have broad relevance for understanding how cells respond to lysosome dysfunction in both normal physiology and disease. In particular, expansion of a hexanucleotide repeat in a non-coding region of the C9orf72 gene is the most common familial cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) identified to date. The current lack of understanding of C9orf72 protein function is a major obstacle to understanding the potential impact of reduced C9orf72 protein levels in the development of these neurodegenerative diseases. The results of our experiments are expected to yield direct targets of C9orf72 and will thereby provide a foundation for the evaluation of their dysregulation in the context of neurodegenerative disease. Beyond addressing specific questions about C9orf72 protein function and neurodegenerative disease, elucidation of fundamental mechanisms that match lysosome function to ongoing changes in cellular demand is of broad cell biological importance with potential relevance for multiple physiological and pathological contexts.