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

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

doi:10.1186/s40478-021-01148-z

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

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

Research output: Contribution to journal › Article › peer-review

3 Scopus citations

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.

Original language	English (US)
Article number	52
Journal	Acta neuropathologica communications
Volume	9
Issue number	1
DOIs	https://doi.org/10.1186/s40478-021-01148-z
State	Published - Dec 2021

Keywords

ALS
Drosophila
Glypican
Motor neuron
Neuromuscular junction
TDP-43
Translation
Wnt signaling

ASJC Scopus subject areas

Pathology and Forensic Medicine
Clinical Neurology
Cellular and Molecular Neuroscience

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10.1186/s40478-021-01148-z

Cite this

Lehmkuhl, E. M., Loganathan, S., Alsop, E., Blythe, A. D., Kovalik, T., Mortimore, N. P., Barrameda, D., Kueth, C., Eck, R. J., Siddegowda, B. B., Joardar, A., Ball, H., Macias, M. E., Bowser, R., Van Keuren-Jensen, K., & Zarnescu, D. C. (2021). TDP-43 proteinopathy alters the ribosome association of multiple mRNAs including the glypican Dally-like protein (Dlp)/GPC6. Acta neuropathologica communications, 9(1), [52]. https://doi.org/10.1186/s40478-021-01148-z

Lehmkuhl, EM, Loganathan, S, Alsop, E, Blythe, AD, Kovalik, T, Mortimore, NP, Barrameda, D, Kueth, C, Eck, RJ, Siddegowda, BB, Joardar, A, Ball, H, Macias, ME, Bowser, R, Van Keuren-Jensen, K & Zarnescu, DC 2021, 'TDP-43 proteinopathy alters the ribosome association of multiple mRNAs including the glypican Dally-like protein (Dlp)/GPC6', Acta neuropathologica communications, vol. 9, no. 1, 52. https://doi.org/10.1186/s40478-021-01148-z

@article{07d730f113614dc2a192eeb76b3315ee,

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

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.",

keywords = "ALS, Drosophila, Glypican, Motor neuron, Neuromuscular junction, TDP-43, Translation, Wnt signaling",

author = "Lehmkuhl, {Erik M.} and Suvithanandhini Loganathan and Eric Alsop and Blythe, {Alexander D.} and Tina Kovalik and Mortimore, {Nicholas P.} and Dianne Barrameda and Chuol Kueth and Eck, {Randall J.} and Siddegowda, {Bhavani B.} and Archi Joardar and Hannah Ball and Macias, {Maria E.} and Robert Bowser and {Van Keuren-Jensen}, Kendall and Zarnescu, {Daniela C.}",

note = "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: {\textcopyright} 2021, The Author(s).",

year = "2021",

month = dec,

doi = "10.1186/s40478-021-01148-z",

language = "English (US)",

volume = "9",

journal = "Acta neuropathologica communications",

issn = "2051-5960",

publisher = "BioMed Central",

number = "1",

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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 - 10.1186/s40478-021-01148-z

DO - 10.1186/s40478-021-01148-z

M3 - Article

C2 - 33762006

AN - SCOPUS:85103038645

SN - 2051-5960

VL - 9

JO - Acta neuropathologica communications

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ER -

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

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Additional file 3 of TDP-43 proteinopathy alters the ribosome association of multiple mRNAs including the glypican Dally-like protein (Dlp)/GPC6

Additional file 4 of TDP-43 proteinopathy alters the ribosome association of multiple mRNAs including the glypican Dally-like protein (Dlp)/GPC6

Cite this

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

Abstract

Keywords

ASJC Scopus subject areas

Access to Document

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Additional file 2 of TDP-43 proteinopathy alters the ribosome association of multiple mRNAs including the glypican Dally-like protein (Dlp)/GPC6

Additional file 3 of TDP-43 proteinopathy alters the ribosome association of multiple mRNAs including the glypican Dally-like protein (Dlp)/GPC6

Additional file 4 of TDP-43 proteinopathy alters the ribosome association of multiple mRNAs including the glypican Dally-like protein (Dlp)/GPC6

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