Lysosomal Regulation and Functions for TBK1 in Neurodegenerative Diseases

Yale University, New Haven CT

Investigators

Abstract

Abstract Lysosomes degrade and recycle macromolecules, clearing harmful materials and providing nutrients, while also communicating nutrient availability to the cell. Although these functions are critical in all tissues, the aging central nervous system is particularly sensitive to lysosome disruptions. This sensitivity is evident in the wide range of neurodegenerative diseases caused by mutations in genes encoding lysosomal proteins. A significant challenge in developing new therapies from these genetic insights is the limited understanding of the fundamental cellular processes affected by disease genes and the consequences of perturbing these processes in specialized types of brain cells. Identifying pathways where disease-causing genes converge is thus crucial for developing therapies that target the cellular vulnerabilities underlying disease susceptibility and progression. Our research focuses on TANK-binding kinase 1 (TBK1) and C9orf72, two genes whose mutations cause amyotrophic lateral sclerosis and frontotemporal dementia (ALS-FTD). We have identified a novel pathway where TBK1 signals at the lysosome surface. Additionally, we have found that C9orf72 regulates this lysosomal pool of TBK1 and identified other activators of TBK1 at lysosomes, including nutrients, lysosome damage, and innate immunity signaling. We aim to elucidate the molecular mechanisms that integrate these signals to activate TBK1 at lysosomes. We also seek to understand the contributions of this signaling to lysosome functions in neurons and glia and to identify the targets of TBK1 kinase activity that mediate its effects on lysosomes. To address these issues, we will use genome-edited cell lines to establish the molecular mechanisms by which TBK1 coordinate lysosome function with cellular demand. These mechanistic studies will be complemented with experiments in genome-edited human induced pluripotent stem cells (iPSCs) and neurons and glia derived from them. This research will define a new pathway in which TBK1 helps match lysosome function to cellular demand, potentially revealing novel mechanisms for controlling lysosome function in ALS-FTD. Given the broader role of endolysosomal pathway dysfunction across multiple neurodegenerative diseases, our findings are likely to be relevant beyond diseases directly caused by mutations in C9orf72 and TBK1.