Project Summary Tweety Homolog 1 (TTYH1) is an understudied protein identified by the Illuminating the Druggable Genome (IDG) Program. Our current knowledge on TTYH1 is limited to its involvement in neural stem cell development and glioma invasion. Given the lack of model system and genetic tools, molecular function and biological pathways that are associated with TTYH1 remain poorly defined. Importantly, altered expression levels of TTYH1 have been found in brain samples from Alzheimer’s disease and Parkinson’s disease patients. Therefore, elucidating the functional roles of TTYH1 in brain cells will aid in the understanding of disease pathogenesis. We performed transcriptomic analyses and determined that TTYH1 is predominantly expressed in brain astrocytes. Astrocytes are glial cells responsible for processing lipids and providing metabolic support to neurons. In Drosophila glia, immortalized rat astrocytes, and primary human astrocytes, we found that TTYH1 orthologs are localized to lysosome, the organelle required for performing autophagy. Indeed, we found that TTYH1 facilitates autophagic flux in glial cells. Delineating the mechanistic underpinnings of autophagy regulation will uncover the molecular function and biological role of TTYH1. Our data suggest that defective clearance of internalized sphingolipids underlies lysosomal dysfunction and diminished autophagy in TTYH1- deficient glial cells. The preliminary findings inform our central hypothesis that TTYH1 mediates lysosomal clearance of sphingolipids to facilitate autophagy. To test our working hypothesis, we will leverage rat astrocytic cell model and Drosophila model combined with tools and experimental paradigms developed for this project. At the conclusion of this investigation, we will have furthered our understanding of the molecular function of TTYH1 in glial lipid metabolism. Findings from this project will also offer insights to understanding lysosomal storage diseases and neurodegeneration.

Project Narrative TTYH1 is highly expressed by astrocyte, the metabolic workhorse of the brain. Our understanding of how TTYH1 participates in glial cell metabolism remains limited. This project aims at elucidating the role of TTYH1 in glial cell autophagy, a key homeostasis process for lipid metabolism.