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.
authors.affiliation: Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048, USA.
authors.forename: Jacqueline G
authors.initials: JG
authors.lastname: O'Rourke
authors.affiliation: The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609, USA.
authors.forename: Laurent
authors.initials: L
authors.lastname: Bogdanik
authors.affiliation: Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048, USA.
authors.forename: A K M G
authors.initials: AKMG
authors.lastname: Muhammad
authors.affiliation: Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA.
authors.forename: Tania F
authors.initials: TF
authors.lastname: Gendron
authors.affiliation: Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048, USA.
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Kim
authors.affiliation: The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Austin
authors.affiliation: Department of Neurology, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, USA.
authors.forename: Janet
authors.initials: J
authors.lastname: Cady
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Elaine Y
authors.initials: EY
authors.lastname: Liu
authors.affiliation: Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048, USA.
authors.forename: Jonah
authors.initials: J
authors.lastname: Zarrow
authors.affiliation: Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048, USA.
authors.forename: Sharday
authors.initials: S
authors.lastname: Grant
authors.affiliation: Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048, USA.
authors.forename: Ritchie
authors.initials: R
authors.lastname: Ho
authors.affiliation: Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048, USA.
authors.forename: Shaughn
authors.initials: S
authors.lastname: Bell
authors.affiliation: Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048, USA.
authors.forename: Sharon
authors.initials: S
authors.lastname: Carmona
authors.affiliation: Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048, USA.
authors.forename: Megan
authors.initials: M
authors.lastname: Simpkinson
authors.affiliation: Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048, USA.
authors.forename: Deepti
authors.initials: D
authors.lastname: Lall
authors.affiliation: Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048, USA.
authors.forename: Kathryn
authors.initials: K
authors.lastname: Wu
authors.affiliation: Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA.
authors.forename: Lillian
authors.initials: L
authors.lastname: Daughrity
authors.affiliation: Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA.
authors.forename: Dennis W
authors.initials: DW
authors.lastname: Dickson
authors.affiliation: Department of Neurology, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, USA.
authors.forename: Matthew B
authors.initials: MB
authors.lastname: Harms
authors.affiliation: Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA.
authors.forename: Leonard
authors.initials: L
authors.lastname: Petrucelli
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Edward B
authors.initials: EB
authors.lastname: Lee
authors.affiliation: The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609, USA.
authors.forename: Cathleen M
authors.initials: CM
authors.lastname: Lutz
authors.affiliation: Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048, USA; Department of Neurology, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048, USA. Electronic address: robert.baloh@csmc.edu.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Baloh
mesh_terms: D000367:Age Factors; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology*; D000073885:C9orf72 Protein; D002478:Cells, Cultured; D022202:Chromosomes, Artificial, Bacterial / Q000235:genetics / Q000378:metabolism; D042622:DNA Repeat Expansion / Q000235:genetics*; D004195:Disease Models, Animal; D057180:Frontotemporal Dementia / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology; D018698:Glutamic Acid / Q000494:pharmacology; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009043:Motor Activity / Q000235:genetics; D053580:Muscle Strength / Q000235:genetics; D009469:Neuromuscular Junction / Q000235:genetics / Q000473:pathology; D009474:Neurons / Q000187:drug effects; D011506:Proteins / Q000235:genetics*; D011597:Psychomotor Performance / Q000502:physiology; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology*
chemical_list: D000073885:C9orf72 Protein; C568651:C9orf72 protein, human; D011506:Proteins; D018698:Glutamic Acid