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

• Published in: Acta neuropathologica communications Vol. 9; no. 1; p. 52
• Main Authors: 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, Zarnescu, Daniela C
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 24-03-2021; BioMed Central; BMC
• Subjects: Adaptor Proteins, Signal Transducing - metabolism; ALS; Amyotrophic lateral sclerosis; Amyotrophic Lateral Sclerosis - metabolism; Amyotrophic Lateral Sclerosis - pathology; Analysis; Animals; Deoxyribonucleic acid; DNA; Drosophila; Ethylenediaminetetraacetic acid; Experiments; Genomics; Glycerol; Glypican; Glypicans - metabolism; Heparan sulfate; Humans; Hypotheses; Insects; Localization; Messenger RNA; Metabolism; Motor neuron; Motor Neurons - metabolism; Motor Neurons - pathology; Mutation; Nerve Degeneration - metabolism; Nerve Degeneration - pathology; Nervous system diseases; Neuromuscular junction; Nuclear Proteins - metabolism; Pathogenesis; Protein binding; Proteins; Ribosomes - metabolism; RNA, Messenger - metabolism; Spinal Cord - metabolism; TDP-43; TDP-43 Proteinopathies - metabolism; TDP-43 Proteinopathies - pathology; Translation; Translation; Wnt signaling; Drosophila; TDP-43; ALS; Glypican; Motor neuron; Neuromuscular junction
• ISSN: 2051-5960; 2051-5960
• DOI: 10.1186/s40478-021-01148-z

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.