Project Details
Description
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.
Status | Finished |
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Effective start/end date | 6/1/23 → 5/31/24 |
Funding
- National Center for Advancing Translational Sciences: $157,000.00
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