@article{7dc2cd0cc09f402d8b5221c2d7a97bc6,
title = "Nucleocytoplasmic Proteomic Analysis Uncovers eRF1 and Nonsense-Mediated Decay as Modifiers of ALS/FTD C9orf72 Toxicity",
abstract = "The most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is a hexanucleotide repeat expansion in C9orf72 (C9-HRE). While RNA and dipeptide repeats produced by C9-HRE disrupt nucleocytoplasmic transport, the proteins that become redistributed remain unknown. Here, we utilized subcellular fractionation coupled with tandem mass spectrometry and identified 126 proteins, enriched for protein translation and RNA metabolism pathways, which collectively drive a shift toward a more cytosolic proteome in C9-HRE cells. Among these was eRF1, which regulates translation termination and nonsense-mediated decay (NMD). eRF1 accumulates within elaborate nuclear envelope invaginations in patient induced pluripotent stem cell (iPSC) neurons and postmortem tissue and mediates a protective shift from protein translation to NMD-dependent mRNA degradation. Overexpression of eRF1 and the NMD driver UPF1 ameliorate C9-HRE toxicity in vivo. Our findings provide a resource for proteome-wide nucleocytoplasmic alterations across neurodegeneration-associated repeat expansion mutations and highlight eRF1 and NMD as therapeutic targets in C9orf72-associated ALS and/or FTD.",
keywords = "C9orf72, ETF1/eRF1, UPF1, amyotrophic lateral sclerosis, frontotemporal dementia, motor neurons, neurodegeneration, nonsense-mediated decay, nuclear invaginations, nucleocytoplasmic proteome",
author = "Ortega, {Juan A.} and Daley, {Elizabeth L.} and Sukhleen Kour and Marisa Samani and Liana Tellez and Smith, {Haley S.} and Hall, {Elizabeth A.} and Esengul, {Y. Taylan} and Tsai, {Yung Hsu} and Gendron, {Tania F.} and Donnelly, {Christopher J.} and Teepu Siddique and Savas, {Jeffrey N.} and Pandey, {Udai B.} and Evangelos Kiskinis",
note = "Funding Information: We are grateful to the following funding sources: the US National Institutes of Health (NIH) and National Institute on Neurological Disorders and Stroke (NINDS) and National Institute on Aging (NIA), United States grant R01NS104219 (E.K.); NIH and NINDS grants R21NS111248 (E.K.) and R21NS107761 (E.K. and J.N.S.); the Les Turner ALS Foundation, United States (E.K.); the Muscular Dystrophy Association, United States (E.K. and U.B.P.); the ALS Association, United States (U.B.P.); the Robert Packard Center for ALS at Johns Hopkins, United States (U.B.P.); NIH grants R01NS081303 (U.B.P.), R21NS098379, NS101661, and NS100055 (U.B.P.); and NIH and NINDS grant R01AG061787 (J.N.S.). We thank Alfred W. Rademaker for advice on statistical analysis and the Allen Cell Collection for providing the LMNB1-mEGFP iPSC line. J.A.O. is a postdoctoral fellow of the French Muscular Dystrophy Association (AFM-T{\'e}l{\'e}thon). E.L.D is supported by the NIH and NIA Mechanisms of Aging and Dementia T32 Training grant AG20506. E.K. is a member of the Simpson Querrey Institute for BioNanotechnology, a Les Turner ALS Research Center Investigator, and a New York Stem Cell Foundation Robertson Investigator. Conceptualization, J.A.O. E.L.D. and E.K.; Methodology and Validation, J.A.O. E.L.D. S.K. J.N.S. U.B.P. and E.K.; Formal Analysis, J.A.O. E.L.D. and E.K.; Investigation, J.A.O. E.L.D. S.K. M.S. L.T. H.S.S. E.A.H. Y.T.E. Y.-H.T. T.F.G. C.J.D. T.S. J.N.S. U.B.P. and E.K.; Resources, Y.T.E. T.F.G. C.J.D. T.S. J.N.S. U.B.P. and E.K.; Writing – Original Draft, J.A.O. E.L.D. and E.K.; Writing – Review & Editing, J.A.O. E.L.D. S.K. M.S. L.T. H.S.S. E.A.H. Y.T.E. Y.-H.T. T.F.G. C.J.D. T.S. J.N.S. U.B.P. and E.K.; Supervision and Project Administration, E.K.; Funding Acquisition, J.N.S. U.B.P. and E.K. The authors declare no competing interests. Funding Information: We are grateful to the following funding sources: the US National Institutes of Health (NIH) and National Institute on Neurological Disorders and Stroke (NINDS) and National Institute on Aging (NIA), United States grant R01NS104219 (E.K.); NIH and NINDS grants R21NS111248 (E.K.) and R21NS107761 (E.K. and J.N.S.); the Les Turner ALS Foundation , United States (E.K.); the Muscular Dystrophy Association , United States (E.K. and U.B.P.); the ALS Association , United States (U.B.P.); the Robert Packard Center for ALS at Johns Hopkins , United States (U.B.P.); NIH grants R01NS081303 (U.B.P.), R21NS098379 , NS101661 , and NS100055 (U.B.P.); and NIH and NINDS grant R01AG061787 (J.N.S.). We thank Alfred W. Rademaker for advice on statistical analysis and the Allen Cell Collection for providing the LMNB1-mEGFP iPSC line. J.A.O. is a postdoctoral fellow of the French Muscular Dystrophy Association (AFM-T{\'e}l{\'e}thon). E.L.D is supported by the NIH and NIA Mechanisms of Aging and Dementia T32 Training grant AG20506. E.K. is a member of the Simpson Querrey Institute for BioNanotechnology, a Les Turner ALS Research Center Investigator, and a New York Stem Cell Foundation Robertson Investigator. Publisher Copyright: {\textcopyright} 2020 Elsevier Inc.",
year = "2020",
month = apr,
day = "8",
doi = "10.1016/j.neuron.2020.01.020",
language = "English (US)",
volume = "106",
pages = "90--107.e13",
journal = "Neuron",
issn = "0896-6273",
publisher = "Cell Press",
number = "1",
}