TDP-43 proteinopathy alters the ribosome association of multiple mRNAs including the glypican Dally-like protein (Dlp)/GPC6
Amyotrophic lateral sclerosis (ALS) is a genetically heterogeneous neurodegenerative disease in which 97% of patients exhibit cytoplasmic aggregates containing the RNA binding protein TDP-43. 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 ribosome association 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.
Acta Neuropathologica Communications
Digital Object Identifier (DOI)
Lehmkuhl, Erik M.; Loganathan, Suvithanandhini; Alsop, Eric; Blythe, Alexander D.; Kovalik, Tina; Mortimore, Nicholas P.; Barrameda, Dianne; Kueth, Chuol; Eck, Randall J.; Siddegowda, Bhavani B.; Joardar, Archi; Ball, Hannah; Macias, Maria E.; Bowser, Robert; Van Keuren-Jensen, Kendall; and Zarnescu, Daniela C., "TDP-43 proteinopathy alters the ribosome association of multiple mRNAs including the glypican Dally-like protein (Dlp)/GPC6" (2021). Translational Neuroscience. 1060.