TY - JOUR
T1 - TDP-43 proteinopathy alters the ribosome association of multiple mRNAs including the glypican Dally-like protein (Dlp)/GPC6
AU - Lehmkuhl, Erik M.
AU - Loganathan, Suvithanandhini
AU - Alsop, Eric
AU - Blythe, Alexander D.
AU - Kovalik, Tina
AU - Mortimore, Nicholas P.
AU - Barrameda, Dianne
AU - Kueth, Chuol
AU - Eck, Randall J.
AU - Siddegowda, Bhavani B.
AU - Joardar, Archi
AU - Ball, Hannah
AU - Macias, Maria E.
AU - Bowser, Robert
AU - Van Keuren-Jensen, Kendall
AU - Zarnescu, Daniela C.
N1 - Funding Information: We thank members of the Zarnescu lab, including Samantha Macklin. Taylor Wingfield, Rebekah Keating Godfrey, Zachary Hammer. Ernesto Manzo, Matthew Scandura, Josh Paree, Alyssa Coyne, and Ben Zaepfel for help with dissections and comments on the manuscript. We also thank Herman Dierick, Takeshi Iwatsubo, Paul Taylor, David Morton and William Orr for providing Drosophila strains. We acknowledge the Bloomington Drosophila Stock Center and the University of Iowa Developmental Studies Hybridoma Bank for supplying reagents. We thank the Barrow Neurological Institute ALS Tissue Bank and Target ALS Postmortem Tissue Core for access to tissues and slides, and all patients for participating in this study. Patty Jansma provided assistance with imaging in the Marley Imaging Core at UArizona. Funding was provided by National Institutes of Health NIH NS091299, NS115514, Sandra Harsha Estate (to DCZ), the ARCS foundation and NIH T32-GM008659 (to EML), the Undergraduate Biology Research Program (to ADB, NM, HB and MEM), the Beckman Scholars Program (to RJE), the UArizona Graduate College Award (to CK), a Muscular Dystrophy Association B2I award (to AJ), Target ALS Foundation (to RB) and donations on behalf of ALS patients (to KJ). Publisher Copyright: © 2021, The Author(s).
PY - 2021/12
Y1 - 2021/12
N2 - 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.
AB - 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.
KW - ALS
KW - Drosophila
KW - Glypican
KW - Motor neuron
KW - Neuromuscular junction
KW - TDP-43
KW - Translation
KW - Wnt signaling
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U2 - https://doi.org/10.1186/s40478-021-01148-z
DO - https://doi.org/10.1186/s40478-021-01148-z
M3 - Article
C2 - 33762006
SN - 2051-5960
VL - 9
JO - Acta neuropathologica communications
JF - Acta neuropathologica communications
IS - 1
M1 - 52
ER -