G4C2 Repeat RNA Initiates a POM121-Mediated Reduction in Specific Nucleoporins in C9orf72 ALS/FTD

Alyssa N. Coyne, Benjamin L. Zaepfel, Lindsey Hayes, Boris Fitchman, Yuval Salzberg, En Ching Luo, Kelly Bowen, Hannah Trost, Stefan Aigner, Frank Rigo, Gene W. Yeo, Amnon Harel, Clive N. Svendsen, Dhruv Sareen, Jeffrey D. Rothstein

Research output: Contribution to journalArticlepeer-review

82 Scopus citations

Abstract

Coyne et al. demonstrate that G4C2 repeat RNA initiates a reduction of POM121 expression within C9orf72 neuronal nuclear pore complexes. Decreased nuclear POM121 affects the expression of seven additional nucleoporins, resulting in altered nuclear pore composition. This combined nucleoporin reduction affects the localization of nucleocytoplasmic transport proteins and neuronal survival.

Original languageEnglish
Pages (from-to)1124-1140.e11
JournalNeuron
Volume107
Issue number6
DOIs
StatePublished - 23 Sep 2020

Bibliographical note

Publisher Copyright:
© 2020 Elsevier Inc.

Funding

We thank the ALS patients and their families for essential contributions to this research and the Target ALS Human Postmortem Tissue Core and Jonathan Glass (Emory University; ADRC NIH P50 AG025688-11REV ) for providing postmortem human tissue. We also thank Martin Hetzer, Adrian Isaacs, Davide Trotti, and Maurice Swanson for kindly gifting POM121, G 4 C 2 RNA Only, DPR, and (CTG) 202 plasmids, respectively. Expert technical assistance for iPSC maintenance was provided by Xiaopei Tang and Weibo Zhou. We thank Patrick Lusk for helpful comments in the editing of this manuscript. This work was supported by the ALSA Milton Safenowitz Postdoctoral Fellowship (ANC), a research grant from the Israel Science Foundation ( 958/15 ) to A.H., and with funding to J.D.R. from NIH-NINDS ( RF1AG062171 , P01NS099114 , and R01NS094239 ), The Robert Packard Center for ALS Research Answer ALS Program , ALS Finding a Cure , ALS Association , Muscular Dystrophy Association , F Prime, and the Chan Zuckerberg Initiative . We thank the ALS patients and their families for essential contributions to this research and the Target ALS Human Postmortem Tissue Core and Jonathan Glass (Emory University; ADRC NIH P50 AG025688-11REV) for providing postmortem human tissue. We also thank Martin Hetzer, Adrian Isaacs, Davide Trotti, and Maurice Swanson for kindly gifting POM121, G4C2 RNA Only, DPR, and (CTG)202 plasmids, respectively. Expert technical assistance for iPSC maintenance was provided by Xiaopei Tang and Weibo Zhou. We thank Patrick Lusk for helpful comments in the editing of this manuscript. This work was supported by the ALSA Milton Safenowitz Postdoctoral Fellowship (ANC), a research grant from the Israel Science Foundation (958/15) to A.H. and with funding to J.D.R. from NIH-NINDS (RF1AG062171, P01NS099114, and R01NS094239), The Robert Packard Center for ALS Research Answer ALS Program, ALS Finding a Cure, ALS Association, Muscular Dystrophy Association, F Prime, and the Chan Zuckerberg Initiative. Conceived and designed the experiments: A.N.C. and J.D.R. Performed the experiments: A.N.C. B.L.Z. L.H. B.F. E.-C.L. and H.T. Analyzed the data: A.N.C. Y.S. K.B. H.T. D.S. and J.D.R. Contributed reagents and materials: A.N.C. B.L.Z. L.H. S.A. F.R. D.S. C.N.S. G.W.Y. A.H. and J.D.R. Wrote the manuscript: A.N.C. and J.D.R. with input from co-authors. The authors declare no competing interests.

FundersFunder number
ADRC NIHP50 AG025688-11REV
Maurice SwansonPOM121
NIH-NINDSP01NS099114, RF1AG062171
National Institute of Neurological Disorders and StrokeR01NS094239
Amyotrophic Lateral Sclerosis Association
Muscular Dystrophy Association
Israel Science Foundation958/15

    Keywords

    • ALS
    • C9orf72
    • FTD
    • POM121
    • neurodegeneration
    • nuclear pore complex

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