Lost in Translation: Variations in WNT Signaling and Other Translational Changes in a Drosophila Model of ALS

Abstract

Amyotrophic 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.