title: Neurodegeneration in frontotemporal lobar degeneration and motor neurone disease associated with expansions in C9orf72 is linked to TDP-43 pathology and not associated with aggregated forms of dipeptide repeat proteins.
abstract: OBJECTIVE
  A hexanucleotide expansion in C9orf72 is the major genetic cause of inherited behavioural variant Frontotemporal dementia (bvFTD) and motor neurone disease (MND), although the pathological mechanism(s) underlying disease remains uncertain.
  
  
  METHODS
  Using antibodies to poly-GA, poly-GP, poly-GR, poly-AP and poly-PR proteins, we examined sections of cerebral cortex, hippocampus, thalamus, cerebellum and spinal cord, from 20 patients with bvFTD and/or MND bearing an expansion in C9orf72 for aggregated deposits of dipeptide repeat proteins (DPR).
  
  
  RESULTS
  Antibodies to poly-GA, poly-GP and poly-GR detected numerous rounded cytoplasmic inclusions (NCI) within granule cells of hippocampal dentate gyrus and those of the cerebellum, as well as 'star-burst' shaped NCI in pyramidal neurones of CA3/4 region of hippocampus. NCI were uncommon in Purkinje cells, and only very rarely seen in anterior horn cells. Poly-PA antibody detected occasional NCI within CA3/4 neurones alone, whereas poly-PR antibody did not identify any NCI but immunostained the nucleus of anterior horn cells, CA3/4 neurones and Purkinje cells, in patients with or without expansion in C9orf72, as well as in normal controls. Poly-GA antibody generally detected more DPR than poly-GP, which in turn was greater than poly-GR. All patients with bvFTD + MND or MND showed plentiful p62/TDP-43 positive inclusions in remaining anterior horn cells.
  
  
  CONCLUSIONS
  Degeneration and loss of anterior horn cells associated with expansions in C9orf72 occurs in the absence of DPR, and implies that changes involving loss of nuclear staining for and a cytoplasmic aggregation of TDP-43 are more likely to be the cause of this.
authors.affiliation: Clinical and Cognitive Sciences Research Group, Institute of Brain, Behaviour and Mental Health, Faculty of Medical and Human Sciences, University of Manchester, Salford Royal Hospital, Salford, UK.
authors.forename: Y
authors.initials: Y
authors.lastname: Davidson
authors.affiliation: Clinical and Cognitive Sciences Research Group, Institute of Brain, Behaviour and Mental Health, Faculty of Medical and Human Sciences, University of Manchester, Salford Royal Hospital, Salford, UK.
authors.forename: A C
authors.initials: AC
authors.lastname: Robinson
authors.affiliation: Clinical and Cognitive Sciences Research Group, Institute of Brain, Behaviour and Mental Health, Faculty of Medical and Human Sciences, University of Manchester, Salford Royal Hospital, Salford, UK.|Beijing University of Chinese Medicine, Dongzhimen Hospital, Beijing, China.
authors.forename: X
authors.initials: X
authors.lastname: Liu
authors.affiliation: Clinical and Cognitive Sciences Research Group, Institute of Brain, Behaviour and Mental Health, Faculty of Medical and Human Sciences, University of Manchester, Salford Royal Hospital, Salford, UK.|Beijing University of Chinese Medicine, Dongzhimen Hospital, Beijing, China.
authors.forename: D
authors.initials: D
authors.lastname: Wu
authors.affiliation: London Neurodegenerative Diseases Brain Bank, Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
authors.forename: C
authors.initials: C
authors.lastname: Troakes
authors.affiliation: Clinical and Cognitive Sciences Research Group, Institute of Brain, Behaviour and Mental Health, Faculty of Medical and Human Sciences, University of Manchester, Manchester, UK.
authors.forename: S
authors.initials: S
authors.lastname: Rollinson
authors.affiliation: Department of Neuropathology and Cell Biology, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Masuda-Suzukake
authors.affiliation: Department of Neuropathology and Cell Biology, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.
authors.forename: G
authors.initials: G
authors.lastname: Suzuki
authors.affiliation: Department of Neuropathology and Cell Biology, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Nonaka
authors.affiliation: Beijing University of Chinese Medicine, Dongzhimen Hospital, Beijing, China.
authors.forename: J
authors.initials: J
authors.lastname: Shi
authors.affiliation: Beijing University of Chinese Medicine, Dongzhimen Hospital, Beijing, China.
authors.forename: J
authors.initials: J
authors.lastname: Tian
authors.affiliation: Manchester MND Care Centre, Salford Royal Hospital, Manchester, UK.
authors.forename: H
authors.initials: H
authors.lastname: Hamdalla
authors.affiliation: Manchester MND Care Centre, Salford Royal Hospital, Manchester, UK.
authors.forename: J
authors.initials: J
authors.lastname: Ealing
authors.affiliation: Cerebral Function Unit, Salford Royal Hospital, Manchester, UK.
authors.forename: A
authors.initials: A
authors.lastname: Richardson
authors.affiliation: Cerebral Function Unit, Salford Royal Hospital, Manchester, UK.
authors.forename: M
authors.initials: M
authors.lastname: Jones
authors.affiliation: Clinical and Cognitive Sciences Research Group, Institute of Brain, Behaviour and Mental Health, Faculty of Medical and Human Sciences, University of Manchester, Manchester, UK.
authors.forename: S
authors.initials: S
authors.lastname: Pickering-Brown
authors.affiliation: Clinical and Cognitive Sciences Research Group, Institute of Brain, Behaviour and Mental Health, Faculty of Medical and Human Sciences, University of Manchester, Salford Royal Hospital, Salford, UK.|Cerebral Function Unit, Salford Royal Hospital, Manchester, UK.
authors.forename: J S
authors.initials: JS
authors.lastname: Snowden
authors.affiliation: Department of Neuropathology and Cell Biology, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Hasegawa
authors.affiliation: Clinical and Cognitive Sciences Research Group, Institute of Brain, Behaviour and Mental Health, Faculty of Medical and Human Sciences, University of Manchester, Salford Royal Hospital, Salford, UK.
authors.forename: D M A
authors.initials: DM
authors.lastname: Mann
mesh_terms: D000368:Aged; D000073885:C9orf72 Protein; D042622:DNA Repeat Expansion; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004151:Dipeptides; D005260:Female; D057174:Frontotemporal Lobar Degeneration / Q000235:genetics / Q000473:pathology*; D006801:Humans; D007150:Immunohistochemistry; D002479:Inclusion Bodies / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D016472:Motor Neuron Disease / Q000235:genetics / Q000473:pathology*; D009410:Nerve Degeneration / Q000235:genetics / Q000473:pathology*; D009474:Neurons / Q000473:pathology; D011506:Proteins / Q000235:genetics*
chemical_list: D000073885:C9orf72 Protein; C568651:C9orf72 protein, human; D004268:DNA-Binding Proteins; D004151:Dipeptides; D011506:Proteins; C000598624:TARDBP protein, human
keywords: C9orf72; TDP-43; dipeptide repeat proteins; frontotemporal lobar degeneration; motor neurone disease