@article{184899d377d34ea9ba22bfcdb4962eee,
title = "Spt4 selectively regulates the expression of C9orf72 sense and antisense mutant transcripts",
abstract = "An expanded hexanucleotide repeat in C9orf72 causes amyotrophic lateral sclerosis and frontotemporal dementia (c9FTD/ALS). Therapeutics are being developed to target RNAs containing the expanded repeat sequence (GGGGCC); however, this approach is complicated by the presence of antisense strand transcription of expanded GGCCCC repeats.We found that targeting the transcription elongation factor Spt4 selectively decreased production of both sense and antisense expanded transcripts, as well as their translated dipeptide repeat (DPR) products, and also mitigated degeneration in animal models. Knockdown of SUPT4H1, the human Spt4 ortholog, similarly decreased production of sense and antisense RNA foci, as well as DPR proteins, in patient cells. Therapeutic targeting of a single factor to eliminate c9FTD/ALS pathological features offers advantages over approaches that require targeting sense and antisense repeats separately.",
author = "Kramer, {Nicholas J.} and Yari Carlomagno and Zhang, {Yong Jie} and Sandra Almeida and Cook, {Casey N.} and Gendron, {Tania F.} and Mercedes Prudencio and {Van Blitterswijk}, Marka and Veronique Belzil and Julien Couthouis and Paul, {Joseph West} and Goodman, {Lindsey D.} and Lillian Daughrity and Jeannie Chew and Aliesha Garrett and Luc Pregent and Karen Jansen-West and Tabassian, {Lilia J.} and Rosa Rademakers and Kevin Boylan and Graff-Radford, {Neill R.} and Josephs, {Keith A.} and Parisi, {Joseph E.} and Knopman, {David S.} and Petersen, {Ronald C.} and Boeve, {Bradley F.} and Ning Deng and Yanan Feng and Cheng, {Tzu Hao} and Dickson, {Dennis W.} and Cohen, {Stanley N.} and Bonini, {Nancy M.} and Link, {Christopher D.} and Gao, {Fen Biao} and Leonard Petrucelli and Gitler, {Aaron D.}",
note = "Funding Information: We thank D. Cerza and Y. Zu for technical support. This work was supported by NIH grants R01NS065317 (A.D.G.), R01NS09386501 (A.D.G., L.P.), R01NS073660 (A.D.G., N.M.B.), R01AG026251 (L.P.), R21NS079807 (Y.-J.Z.), R21NS094489 (C.N.C.), R01NS063964 (L.P.), R01NS077402 (L.P.), R21NS084528 (L.P.), P01NS084974 (L.P.), R01NS088689 (L.P.), R01ES20395 (L.P.), R01NS085812 (S.N.C. and T.-H.C.), R01NS079725 (F.-B.G.), Mayo Clinic Foundation (L.P.), Alzheimer's Association [NIRP-14-304425 (Y.-J.Z.)], Amyotrophic Lateral Sclerosis Association (Y.-J.Z, T.F.G., M.P., L.P., F.-B.G.), the National Science Foundation Graduate Research Fellowship (N.J.K.), the Robert Packard Center for ALS Research at Johns Hopkins (L.P., A.D.G., F.-B.G.), Target ALS (L.P., A.D.G., N.B., F.-B.G.), Association for Frontotemporal Degeneration (S.A.), Stanford University (S.N.C.), and the Glenn Foundation (A.D.G., N.M.B). The induced pluripotent stem cell (iPSC) lines are available from the Gao laboratory under a material transfer agreement with the University of Massachusetts Medical School. R.C.P. has paid consulting relationships with Hoffmann-La Roche, Inc.; Merck, Inc.; Genentech, Inc.; Biogen, Inc.; and Eli Lilly & Co. RNA sequencing data are deposited with the National Center for Biotechnology Information Gene Expression Omnibus (GSE83484).",
year = "2016",
month = aug,
day = "12",
doi = "10.1126/science.aaf7791",
language = "English",
volume = "353",
pages = "708--712",
journal = "Science",
issn = "0036-8075",
publisher = "American Association for the Advancement of Science",
number = "6300",
}