title: C9orf72 ablation in mice does not cause motor neuron degeneration or motor deficits.
abstract: OBJECTIVE
  How hexanucleotide (GGGGCC) repeat expansions in C9ORF72 cause amyotrophic lateral sclerosis (ALS) remains poorly understood. Both gain- and loss-of-function mechanisms have been proposed. Evidence supporting these mechanisms in vivo is, however, incomplete. Here we determined the effect of C9orf72 loss-of-function in mice.
  
  
  METHODS
  We generated and analyzed a conditional C9orf72 knockout mouse model. C9orf72(fl/fl) mice were crossed with Nestin-Cre mice to selectively remove C9orf72 from neurons and glial cells. Immunohistochemistry was performed to study motor neurons and neuromuscular integrity, as well as several pathological hallmarks of ALS, such as gliosis and TDP-43 mislocalization. In addition, motor function and survival were assessed.
  
  
  RESULTS
  Neural-specific ablation of C9orf72 in conditional C9orf72 knockout mice resulted in significantly reduced body weight but did not induce motor neuron degeneration, defects in motor function, or altered survival.
  
  
  CONCLUSIONS
  Our data suggest that C9orf72 loss-of-function, by itself, is insufficient to cause motor neuron disease. These results may have important implications for the development of therapeutic strategies for C9orf72-associated ALS.
authors.affiliation: Department of Translational Neuroscience, University Medical Center Utrecht, Utrecht, the Netherlands.|Department of Neurology and Neurosurgery, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: Max
authors.initials: M
authors.lastname: Koppers
authors.affiliation: Department of Translational Neuroscience, University Medical Center Utrecht, Utrecht, the Netherlands.|Department of Neurology and Neurosurgery, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: Anna M
authors.initials: AM
authors.lastname: Blokhuis
authors.affiliation: Department of Neurology and Neurosurgery, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: Henk-Jan
authors.initials: HJ
authors.lastname: Westeneng
authors.affiliation: Department of Translational Neuroscience, University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: Margo L
authors.initials: ML
authors.lastname: Terpstra
authors.affiliation: Department of Translational Neuroscience, University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: Caroline A C
authors.initials: CA
authors.lastname: Zundel
authors.affiliation: Department of Translational Neuroscience, University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: Renata
authors.initials: R
authors.lastname: Vieira de Sá
authors.affiliation: Department of Neurology and Neurosurgery, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: Raymond D
authors.initials: RD
authors.lastname: Schellevis
authors.affiliation: Institute of Psychological Medicine and Clinical Neurosciences, Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, School of Medicine, Cardiff University, Cardiff, United Kingdom.
authors.forename: Adrian J
authors.initials: AJ
authors.lastname: Waite
authors.affiliation: Institute of Psychological Medicine and Clinical Neurosciences, Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, School of Medicine, Cardiff University, Cardiff, United Kingdom.
authors.forename: Derek J
authors.initials: DJ
authors.lastname: Blake
authors.affiliation: Department of Neurology and Neurosurgery, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: Jan H
authors.initials: JH
authors.lastname: Veldink
authors.affiliation: Department of Neurology and Neurosurgery, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: Leonard H
authors.initials: LH
authors.lastname: van den Berg
authors.affiliation: Department of Translational Neuroscience, University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: R Jeroen
authors.initials: RJ
authors.lastname: Pasterkamp
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000073885:C9orf72 Protein; D055786:Gene Knockout Techniques; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D016472:Motor Neuron Disease / Q000235:genetics* / Q000473:pathology*; D009046:Motor Neurons / Q000473:pathology; D009410:Nerve Degeneration / Q000235:genetics* / Q000473:pathology*; D011506:Proteins / Q000235:genetics*
chemical_list: D000073885:C9orf72 Protein; C568651:C9orf72 protein, human; D011506:Proteins