@article{2a196d537aaa404fb3a537a932dc2387,
title = "C9orf72 BAC Transgenic Mice Display Typical Pathologic Features of ALS/FTD",
abstract = "Noncoding expansions of a hexanucleotide repeat (GGGGCC) in the C9orf72 gene are the most common cause of familial amyotrophic lateral sclerosis and frontotemporal dementia. Here we report transgenic mice carrying a bacterial artificial chromosome (BAC) containing the full human C9orf72 gene with either a normal allele (15 repeats) or disease-associated expansion (∼100-1,000 repeats; C9-BACexp). C9-BACexp mice displayed pathologic features seen in C9orf72 expansion patients, including widespread RNA foci and repeat-associated non-ATG (RAN) translated dipeptides, which were suppressed by antisense oligonucleotides targeting human C9orf72. Nucleolin distribution was altered, supporting that either C9orf72 transcripts or RAN dipeptides promote nucleolar dysfunction. Despite early and widespread production of RNA foci and RAN dipeptides in C9-BACexp mice, behavioral abnormalities and neurodegeneration were not observed even at advanced ages, supporting the hypothesis that RNA foci and RAN dipeptides occur presymptomatically and are not sufficient to drive neurodegeneration in mice at levels seen in patients.",
author = "O'Rourke, {Jacqueline G.} and Laurent Bogdanik and Muhammad, {A. K.M.G.} and Gendron, {Tania F.} and Kim, {Kevin J.} and Andrew Austin and Janet Cady and Liu, {Elaine Y.} and Jonah Zarrow and Sharday Grant and Ritchie Ho and Shaughn Bell and Sharon Carmona and Megan Simpkinson and Deepti Lall and Kathryn Wu and Lillian Daughrity and Dickson, {Dennis W.} and Harms, {Matthew B.} and Leonard Petrucelli and Lee, {Edward B.} and Lutz, {Cathleen M.} and Baloh, {Robert H.}",
note = "Funding Information: We would like to thank Uthra Rajamani and Dhruv Sareen for assistance with the ImageXpress, David Rushton and Virginia Mattis for assistance with the primary cortical cultures, Vince Funari for assistance with RNA-sequencing, and Frank Bennett and Frank Rigo of Isis Pharmaceuticals for supplying antisense oligonucleotides. This work was supported by National Institutes of Health (NIH) Grants NS055980 and NS069669 (R.H.B.), AG039510 (E.B.L.), AG000255 (E.Y.L.), NS089979 (T.F.G.), NS084528 (L.P.), NS063964 (L.P.), NS077402 (L.P.), NS084974 (L.P.), and ES20395 (L.P.); Department of Defense ALSRP AL130125 (L.P.); the Mayo Clinic Foundation (L.P.); Mayo Clinic Center for Individualized Medicine (L.P.); ALS Association (L.P., T.F.G.); Robert Packard Center for ALS Research at Johns Hopkins (L.P.); Target ALS (L.P., R.H.B.); the Robert and Louise Schwab Family (R.H.B.); and the Cedars-Sinai ALS Research Fund (R.H.B.). The project was supported by the National Center for Advancing Translational Sciences, Grant UL1TR000124. Publisher Copyright: {\textcopyright} 2015 Elsevier Inc.",
year = "2015",
month = dec,
day = "2",
doi = "10.1016/j.neuron.2015.10.027",
language = "English (US)",
volume = "88",
pages = "892--901",
journal = "Neuron",
issn = "0896-6273",
publisher = "Cell Press",
number = "5",
}