학술논문
TDP-43 proteinopathy alters the ribosome association of multiple mRNAs including the glypican Dally-like protein (Dlp)/GPC6.
Document Type
Article
Author
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.
Source
Subject
*RNA-binding proteins
*AMYOTROPHIC lateral sclerosis
*MOTOR neurons
*SPINAL cord
*RIBOSOMES
*OXIDATIVE phosphorylation
*NEURODEGENERATION
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Language
ISSN
2051-5960
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. [ABSTRACT FROM AUTHOR]