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 language | English |
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Pages (from-to) | 1124-1140.e11 |
Journal | Neuron |
Volume | 107 |
Issue number | 6 |
DOIs | |
State | Published - 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.
Funders | Funder number |
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ADRC NIH | P50 AG025688-11REV |
Maurice Swanson | POM121 |
NIH-NINDS | P01NS099114, RF1AG062171 |
National Institute of Neurological Disorders and Stroke | R01NS094239 |
Amyotrophic Lateral Sclerosis Association | |
Muscular Dystrophy Association | |
Israel Science Foundation | 958/15 |
Keywords
- ALS
- C9orf72
- FTD
- POM121
- neurodegeneration
- nuclear pore complex