Systems-Level Approach to Neuronopathic Lysosomal Storage Disorders

Neuronopathic lysosomal storage disorders (LSDs) are a group of fatal neurodegenerative diseases caused by genetic defects in components of the lysosome, which is the major site within the cell for the degradation and recycling of exhausted cellular components. Defective lysosomes accumulate undegraded storage material, which has classically been thought to be toxic for the cell and the driver of the pathogenic cascade of the dis- ease. Recent advances in the investigation of the lysosome, however, have shown that the storage burden it- self can be uncoupled from the most dramatic effects of the disease on the affected organs. Moreover, there are emerging roles of the lysosome as a central player in the regulation of cell metabolism which are distinct from its classical role as a cellular degradation site. The central hypothesis of this proposal is that are the changes in the communication between the lysosome and the rest of the cell, rather than the storage itself, that drive disease pathogenesis. Determining exactly which components of the lysosomal communication network mediate disease propagation, in which cell type, and how, is important because it could unveil the next generation of therapeutic targets. We propose to use innovative genetic tools and artificial intelligence-driven analytical pipelines to mechanistically investigate changes in lysosomal content and communication in the central nervous system of mouse models of two distinct LSDs. In Aim 1 we will catalogue LSD-associated changes in lysosomal content and composition and determine their relationship with LSD-specific cellular features based on the perturbation of components of the broad lysosomal gene metabolic network. In Aim 2 we will investigate the changes in the signaling network that mediates communication of the lysosome with the nucleus and determine the effectors of the cell’s response to lysosomal stress. In Aim 3 we will place the study of lysosomal content, signaling, and dysfunction in the context of specific cell types (neurons, astroglia, macrophages) to determine their role in the initiation and propagation of disease. Results from this study will provide the first atlas of changes in lysosomal content and signaling components in LSDs and will pioneer the integrative study of the lysosome as a multi-level network of causally associated components and pathways. Knowledge resulting from this study could lay the foundation for future translational investigation of treatments for neuronopathic LSDs.