TDP-43 proteinopathy alters the ribosome association of multiple mRNAs including the glypican Dally-like protein (Dlp)/GPC6

  • Erik M. Lehmkuhl (Creator)
  • Suvithanandhini Loganathan (Contributor)
  • Eric Alsop (Creator)
  • Alexander D. Blythe (Creator)
  • Tina Kovalik (Creator)
  • Nicholas P. Mortimore (Creator)
  • Dianne Barrameda (Creator)
  • Chuol Kueth (Contributor)
  • Randall J. Eck (Creator)
  • Bhavani Bagevalu Siddegowda (Creator)
  • Archi Joardar (Contributor)
  • Hannah Ball (Creator)
  • Maria E. Macias (Creator)
  • Robert Bowser (Creator)
  • Kendall Van Keuren-Jensen (Contributor)
  • Daniela C Zarnescu (Creator)
  • Kendall Van Keuren-Jensen (Creator)



Abstract 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.
Date made available2021

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