Modulating Cellular Clearance to treat lysosomal storage disorders and neurodegenerative diseases

Cellular clearance is a fundamental process required by the cells of every species. In eukaryotes, most of the cellular clearing processes occur in a specialized organelle, the lysosome. Given that the requirements of the degradative machinery in a cell may vary depending on tissue type, age and environmental conditions, we postulated that a system coordinates lysosomal activity and that lysosomal function is subject to transcriptional regulation. Using a systems biology-based approach, we discovered a gene regulatory network, CLEAR, that controls lysosomal biogenesis and function and a master gene, TFEB, which binds to CLEAR target sites in the promoter of lysosomal genes and positively regulates their expression. TFEB overexpression induces lysosomal biogenesis and increases the cell’s ability to degrade complex molecules.  More recent studies performed in our laboratory have shown that TFEB directly regulates autophagy.  We also demonstrated that TFEB is able to promote cellular clearance in several murine models of LSDs.  The regulation of lysosome-mediated cellular clearance is a new concept in cell biology. Our laboratory is now focused on the study of the regulation and activation of TFEB and on determining mechanisms to activate TFEB function utilizing cell culture systems and in vivo animal models. The challenge of our current research project is to develop tools to modulate cellular clearance and to use them to treat human diseases, including Lysosomal Storage Disorders and neurodegenerative diseases.

The "Total Award" amount indicated for this project represents the share of the funding of the Telethon Foundation for research by the Tigem institute from July 2016 until last budget year, calculated based on the size of the research group.