title: Neurodegeneration. C9ORF72 repeat expansions in mice cause TDP-43 pathology, neuronal loss, and behavioral deficits.
abstract: The major genetic cause of frontotemporal dementia and amyotrophic lateral sclerosis is a G4C2 repeat expansion in C9ORF72. Efforts to combat neurodegeneration associated with "c9FTD/ALS" are hindered by a lack of animal models recapitulating disease features. We developed a mouse model to mimic both neuropathological and clinical c9FTD/ALS phenotypes. We expressed (G4C2)66 throughout the murine central nervous system by means of somatic brain transgenesis mediated by adeno-associated virus. Brains of 6-month-old mice contained nuclear RNA foci, inclusions of poly(Gly-Pro), poly(Gly-Ala), and poly(Gly-Arg) dipeptide repeat proteins, as well as TDP-43 pathology. These mouse brains also exhibited cortical neuron and cerebellar Purkinje cell loss, astrogliosis, and decreased weight. (G4C2)66 mice also developed behavioral abnormalities similar to clinical symptoms of c9FTD/ALS patients, including hyperactivity, anxiety, antisocial behavior, and motor deficits.
authors.affiliation: Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA. Neurobiology of Disease Graduate Program, Mayo Graduate School, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
authors.forename: Jeannie
authors.initials: J
authors.lastname: Chew
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: Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA.
authors.forename: Mercedes
authors.initials: M
authors.lastname: Prudencio
authors.affiliation: Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Sasaguri
authors.affiliation: Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA.
authors.forename: Yong-Jie
authors.initials: YJ
authors.lastname: Zhang
authors.affiliation: Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA.
authors.forename: Monica
authors.initials: M
authors.lastname: Castanedes-Casey
authors.affiliation: Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA.
authors.forename: Chris W
authors.initials: CW
authors.lastname: Lee
authors.affiliation: Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA.
authors.forename: Karen
authors.initials: K
authors.lastname: Jansen-West
authors.affiliation: Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA.
authors.forename: Aishe
authors.initials: A
authors.lastname: Kurti
authors.affiliation: Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA.
authors.forename: Melissa E
authors.initials: ME
authors.lastname: Murray
authors.affiliation: Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA. Neurobiology of Disease Graduate Program, Mayo Graduate School, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
authors.forename: Kevin F
authors.initials: KF
authors.lastname: Bieniek
authors.affiliation: Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA.
authors.forename: Peter O
authors.initials: PO
authors.lastname: Bauer
authors.affiliation: Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA.
authors.forename: Ena C
authors.initials: EC
authors.lastname: Whitelaw
authors.affiliation: Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA.
authors.forename: Linda
authors.initials: L
authors.lastname: Rousseau
authors.affiliation: Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA.
authors.forename: Jeannette N
authors.initials: JN
authors.lastname: Stankowski
authors.affiliation: Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA.
authors.forename: Caroline
authors.initials: C
authors.lastname: Stetler
authors.affiliation: Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA.
authors.forename: Lillian M
authors.initials: LM
authors.lastname: Daughrity
authors.affiliation: Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA.
authors.forename: Emilie A
authors.initials: EA
authors.lastname: Perkerson
authors.affiliation: Department of Neurology, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA.
authors.forename: Pamela
authors.initials: P
authors.lastname: Desaro
authors.affiliation: Department of Neurology, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA.
authors.forename: Amelia
authors.initials: A
authors.lastname: Johnston
authors.affiliation: Department of Neurology, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA.
authors.forename: Karen
authors.initials: K
authors.lastname: Overstreet
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE) Munich, Feodor-Lynen-Strasse 17, 81337 Munich, Germany. Institute for Metabolic Biochemistry, Ludwig-Maximilians University Munich, Feodor-Lynen-Strasse 17, 81337 Munich, Germany. Munich Cluster of Systems Neurology (SyNergy), Munich, Germany.
authors.forename: Dieter
authors.initials: D
authors.lastname: Edbauer
authors.affiliation: Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA. Neurobiology of Disease Graduate Program, Mayo Graduate School, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
authors.forename: Rosa
authors.initials: R
authors.lastname: Rademakers
authors.affiliation: Department of Neurology, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA.
authors.forename: Kevin B
authors.initials: KB
authors.lastname: Boylan
authors.affiliation: Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA. Neurobiology of Disease Graduate Program, Mayo Graduate School, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
authors.forename: Dennis W
authors.initials: DW
authors.lastname: Dickson
authors.affiliation: Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA. Neurobiology of Disease Graduate Program, Mayo Graduate School, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
authors.forename: John D
authors.initials: JD
authors.lastname: Fryer
authors.affiliation: Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA. Neurobiology of Disease Graduate Program, Mayo Graduate School, Mayo Clinic College of Medicine, Rochester, MN 55905, USA. petrucelli.leonard@mayo.edu.
authors.forename: Leonard
authors.initials: L
authors.lastname: Petrucelli
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000473:pathology; D000818:Animals; D000987:Antisocial Personality Disorder / Q000235:genetics / Q000473:pathology; D000073885:C9orf72 Protein; D002540:Cerebral Cortex / Q000378:metabolism / Q000473:pathology; D004268:DNA-Binding Proteins / Q000235:genetics*; D000229:Dependovirus; D004151:Dipeptides / Q000378:metabolism; D004195:Disease Models, Animal; D057180:Frontotemporal Dementia / Q000235:genetics* / Q000473:pathology; D018014:Gene Transfer Techniques; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D011506:Proteins / Q000235:genetics*; D011689:Purkinje Cells / Q000378:metabolism / Q000473:pathology; D015138:RNA, Nuclear / Q000378:metabolism
chemical_list: D000073885:C9orf72 Protein; C568651:C9orf72 protein, human; D004268:DNA-Binding Proteins; D004151:Dipeptides; D011506:Proteins; D015138:RNA, Nuclear; C015248:glycylproline; C065992:N-glycylalanine