title: Human C9ORF72 Hexanucleotide Expansion Reproduces RNA Foci and Dipeptide Repeat Proteins but Not Neurodegeneration in BAC Transgenic Mice.
abstract: A non-coding hexanucleotide repeat expansion in the C9ORF72 gene is the most common mutation associated with familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). To investigate the pathological role of C9ORF72 in these diseases, we generated a line of mice carrying a bacterial artificial chromosome containing exons 1 to 6 of the human C9ORF72 gene with approximately 500 repeats of the GGGGCC motif. The mice showed no overt behavioral phenotype but recapitulated distinctive histopathological features of C9ORF72 ALS/FTD, including sense and antisense intranuclear RNA foci and poly(glycine-proline) dipeptide repeat proteins. Finally, using an artificial microRNA that targets human C9ORF72 in cultures of primary cortical neurons from the C9BAC mice, we have attenuated expression of the C9BAC transgene and the poly(GP) dipeptides. The C9ORF72 BAC transgenic mice will be a valuable tool in the study of ALS/FTD pathobiology and therapy.
authors.affiliation: Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01655, USA.
authors.forename: Owen M
authors.initials: OM
authors.lastname: Peters
authors.affiliation: Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01655, USA.|Department of Pediatrics and Gene Therapy Center University of Massachusetts Medical School, Worcester, MA 01655, USA.
authors.forename: Gabriela Toro
authors.initials: GT
authors.lastname: Cabrera
authors.affiliation: Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01655, USA.
authors.forename: Helene
authors.initials: H
authors.lastname: Tran
authors.affiliation: Department of Neuroscience, Mayo Clinic, 4500 San Pablo Rd., Jacksonville, FL 32224, USA.
authors.forename: Tania F
authors.initials: TF
authors.lastname: Gendron
authors.affiliation: Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01655, USA.
authors.forename: Jeanne E
authors.initials: JE
authors.lastname: McKeon
authors.affiliation: Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01655, USA.
authors.forename: Jake
authors.initials: J
authors.lastname: Metterville
authors.affiliation: Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01655, USA.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Weiss
authors.affiliation: Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01655, USA.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Wightman
authors.affiliation: Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01655, USA.
authors.forename: Johnny
authors.initials: J
authors.lastname: Salameh
authors.affiliation: Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, 21205.
authors.forename: Juyhun
authors.initials: J
authors.lastname: Kim
authors.affiliation: Department of Pediatrics and Gene Therapy Center University of Massachusetts Medical School, Worcester, MA 01655, USA.
authors.forename: Huaming
authors.initials: H
authors.lastname: Sun
authors.affiliation: Department of Neurology, Mayo Clinic, 4500 San Pablo Road, Jacksonville, Florida 32224, USA.
authors.forename: Kevin B
authors.initials: KB
authors.lastname: Boylan
authors.affiliation: Department of Neuroscience, Mayo Clinic, 4500 San Pablo Rd., Jacksonville, FL 32224, USA.
authors.forename: Dennis
authors.initials: D
authors.lastname: Dickson
authors.affiliation: Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01655, USA.
authors.forename: Zack
authors.initials: Z
authors.lastname: Kennedy
authors.affiliation: Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01655, USA.
authors.forename: Ziqiang
authors.initials: Z
authors.lastname: Lin
authors.affiliation: Department of Neuroscience, Mayo Clinic, 4500 San Pablo Rd., Jacksonville, FL 32224, USA.
authors.forename: Yong-Jie
authors.initials: YJ
authors.lastname: Zhang
authors.affiliation: Department of Neuroscience, Mayo Clinic, 4500 San Pablo Rd., Jacksonville, FL 32224, USA.
authors.forename: Lillian
authors.initials: L
authors.lastname: Daughrity
authors.affiliation: Children's Hospital Oakland Research Institute, 5700 Martin Luther King Jr Way, Oakland, California 94609.
authors.forename: Chris
authors.initials: C
authors.lastname: Jung
authors.affiliation: Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01655, USA.
authors.forename: Fen-Biao
authors.initials: FB
authors.lastname: Gao
authors.affiliation: Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01655, USA.|Department of Biology, and McGovern Institute for Brain Research, 77 Massachusetts Avenue, Massachusetts Institute of Technology, Cambridge, MA 02139, H.R.H. is an Investigator of the Howard Hughes Medical Institute.
authors.forename: Peter C
authors.initials: PC
authors.lastname: Sapp
authors.affiliation: Department of Biology, and McGovern Institute for Brain Research, 77 Massachusetts Avenue, Massachusetts Institute of Technology, Cambridge, MA 02139, H.R.H. is an Investigator of the Howard Hughes Medical Institute.
authors.forename: H Robert
authors.initials: HR
authors.lastname: Horvitz
authors.affiliation: Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01655, USA.
authors.forename: Daryl A
authors.initials: DA
authors.lastname: Bosco
authors.affiliation: Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, 21205.
authors.forename: Solange P
authors.initials: SP
authors.lastname: Brown
authors.affiliation: Children's Hospital Oakland Research Institute, 5700 Martin Luther King Jr Way, Oakland, California 94609.
authors.forename: Pieter
authors.initials: P
authors.lastname: de Jong
authors.affiliation: Department of Neuroscience, Mayo Clinic, 4500 San Pablo Rd., Jacksonville, FL 32224, USA.
authors.forename: Leonard
authors.initials: L
authors.lastname: Petrucelli
authors.affiliation: Department of Pediatrics and Gene Therapy Center University of Massachusetts Medical School, Worcester, MA 01655, USA.
authors.forename: Chris
authors.initials: C
authors.lastname: Mueller
authors.affiliation: Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01655, USA.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Brown
mesh_terms: D000367:Age Factors; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000401:mortality / Q000473:pathology / Q000503:physiopathology; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D000073885:C9orf72 Protein; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D022202:Chromosomes, Artificial, Bacterial / Q000235:genetics / Q000378:metabolism; D042622:DNA Repeat Expansion / Q000235:genetics*; D004151:Dipeptides / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D057180:Frontotemporal Dementia / Q000235:genetics* / Q000401:mortality / Q000473:pathology / Q000503:physiopathology; D005786:Gene Expression Regulation / Q000235:genetics; D005838:Genotype; D006801:Humans; D066298:In Vitro Techniques; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D011506:Proteins / Q000235:genetics*
chemical_list: D000073885:C9orf72 Protein; C568651:C9orf72 protein, human; D004151:Dipeptides; D035683:MicroRNAs; D009419:Nerve Tissue Proteins; D011506:Proteins
keywords: Amyotrophic lateral sclerosis (ALS); C9ORF72; RAN translation; RNA foci; frontotemporal dementia (FTD); microRNA; neurodegeneration; repeat expansions; transgenic mice