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

Acta Neuropathologica Communications

Dianne Barrameda¹  Suvithanandhini Loganathan¹  Nicholas P. Mortimore¹  Hannah Ball¹  Bhavani B. Siddegowda¹  Erik M. Lehmkuhl¹  Alexander D. Blythe¹  Archi Joardar¹  Maria E. Macias¹  Chuol Kueth¹  Randall J. Eck¹  Daniela C. Zarnescu²  Tina Kovalik³  Robert Bowser³  Kendall Van Keuren-Jensen⁴  Eric Alsop⁴ 

[1] Department of Cellular and Molecular Biology, University of Arizona, 1007 E. Lowell St, LSS RM 548A, 85721, Tucson, AZ, USA;Department of Cellular and Molecular Biology, University of Arizona, 1007 E. Lowell St, LSS RM 548A, 85721, Tucson, AZ, USA;Department of Neuroscience, University of Arizona, 1040 4th St, 85721, Tucson, AZ, USA;Department of Neurology, University of Arizona, 1501 N Campbell Ave, 85724, Tucson, AZ, USA;Department of Neurobiology, Barrow Neurological Institute, 350 W Thomas Rd, 85013, Phoenix, AZ, USA;Translational Genomics Research Institute, 445 N 5th St, 85004, Phoenix, AZ, USA;

关键词: ALS;    TDP-43;    Translation;    Motor neuron;    Neuromuscular junction;    Glypican;    Wnt signaling;    Drosophila;   

DOI  :  10.1186/s40478-021-01148-z

来源: Springer

【 摘 要 】

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.

【 授权许可】

CC BY