Lost in Translation: Variations in WNT Signaling and Other Translational Changes in a Drosophila Model of ALS
AdvisorZarnescu, Daniela C.
MetadataShow full item record
PublisherThe University of Arizona.
RightsCopyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction, presentation (such as public display or performance) of protected items is prohibited except with permission of the author.
AbstractAmyotrophic lateral sclerosis (ALS) is a genetically heterogeneous neurodegenerative disease inwhich 97% of patients exhibit cytoplasmic aggregates containing the RNA binding protein TDP- 43, referred to as TDP-43 pathology. My project focused on understanding how TDP-43 pathology modifies translation. Using tagged ribosome affinity purifications in Drosophila models of TDP- 43 proteinopathy, we identified TDP-43 dependent translational alterations in motor neurons impacting the spliceosome, pentose phosphate and oxidative phosphorylation pathways. A subset of the mRNAs with altered translation are also enriched in TDP-43 complexes suggesting that they may be direct targets. Among these, dlp mRNA, which encodes the glypican Dally like protein (Dlp)/GPC6, a wingless (Wg/Wnt) signaling regulator is insolubilized both in flies and patient tissues with TDP-43 pathology. While Dlp/GPC6 forms puncta in the Drosophila neuropil and ALS spinal cords, it is reduced at the neuromuscular synapse in flies suggesting compartment specific effects of TDP-43 proteinopathy. These findings together with genetic interaction data show that Dlp/GPC6 is a novel, physiologically relevant target of TDP-43 proteinopathy. Recent further investigation suggests that Dlp puncta represent defunct endomembrane compartments and that TDP-43-Dlp dynamics persist outside of motor neurons.
Degree ProgramGraduate College
Molecular & Cellular Biology