title: Accumulation of dipeptide repeat proteins predates that of TDP-43 in frontotemporal lobar degeneration associated with hexanucleotide repeat expansions in C9ORF72 gene.
abstract: OBJECTIVE
  Frontotemporal lobar degeneration (FTLD) and motor neurone disease are linked by the possession of a hexanucleotide repeat expansion in C9ORF72, and both show neuronal cytoplasmic inclusions within cerebellar and hippocampal neurones which are TDP-43 negative but immunoreactive for p62 and dipeptide repeat proteins (DPR), these being generated by a non-ATG RAN translation of the expanded region of the gene.
  
  
  METHODS
  Twenty-two cases of FTLD from Newcastle were analysed for an expansion in C9ORF72 by repeat primed PCR and Southern blot. Detailed case note analysis was performed, and blinded retrospective clinical impressions were achieved by review of clinical histories. Sections from all major brain regions were immunostained for TDP-43, p62 and DPR. The extent of TDP-43 and DPR pathology in expansion bearers was compared with that in 13 other previously identified cases from the Manchester Brain Bank with established disease.
  
  
  RESULTS
  Three Newcastle patients bearing an expansion in C9ORF72 were identified. These three patients died prematurely, two from bronchopneumonia within 10 months and 3 years of onset, and one from myocardial infarction 3 years after onset. In all three, DPR were plentiful throughout all cerebral cortical regions, hippocampus and cerebellum, but TDP-43 pathological changes were sparse. The severity of DPR pathological changes in these three patients was similar to that in the Manchester series, although the extent of TDP-43 pathology was significantly less.
  
  
  CONCLUSIONS
  Widespread accumulation of DPR within nerve cells may occur much earlier than that of TDP-43 in patients with FTLD bearing expansion in C9ORF72.
authors.affiliation: Department of Neuropathology, Walton Centre for Neurology and Neurosurgery, Liverpool, UK.
authors.forename: Atik
authors.initials: A
authors.lastname: Baborie
authors.affiliation: Institute of Neuroscience, Newcastle University Medical School, Newcastle upon Tyne, UK.
authors.forename: Timothy D
authors.initials: TD
authors.lastname: Griffiths
authors.affiliation: Neuropathology/Cellular Pathology, Royal Victoria Infirmary, Newcastle upon Tyne, UK.|Institute for Ageing and Health, Newcastle University, Campus for Ageing and Vitality, Newcastle upon Tyne, UK.
authors.forename: Evelyn
authors.initials: E
authors.lastname: Jaros
authors.affiliation: Neuropathology/Cellular Pathology, Royal Victoria Infirmary, Newcastle upon Tyne, UK.|Institute for Ageing and Health, Newcastle University, Campus for Ageing and Vitality, Newcastle upon Tyne, UK.
authors.forename: Robert
authors.initials: R
authors.lastname: Perry
authors.affiliation: Institute for Ageing and Health, Newcastle University, Campus for Ageing and Vitality, Newcastle upon Tyne, UK.
authors.forename: Ian G
authors.initials: IG
authors.lastname: McKeith
authors.affiliation: Institute for Ageing and Health, Newcastle University, Campus for Ageing and Vitality, Newcastle upon Tyne, UK.
authors.forename: David J
authors.initials: DJ
authors.lastname: Burn
authors.affiliation: Department of Neuropathology and Cell Biology, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.
authors.forename: Masami
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: Masato
authors.initials: M
authors.lastname: Hasegawa
authors.affiliation: Institute of Brain, Behaviour and Mental Health, University of Manchester, Manchester, UK.
authors.forename: Sara
authors.initials: S
authors.lastname: Rollinson
authors.affiliation: Institute of Brain, Behaviour and Mental Health, University of Manchester, Manchester, UK.
authors.forename: Stuart
authors.initials: S
authors.lastname: Pickering-Brown
authors.affiliation: Institute of Brain, Behaviour and Mental Health, University of Manchester, Salford Royal Hospital, Salford, UK.
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Robinson
authors.affiliation: Institute of Brain, Behaviour and Mental Health, University of Manchester, Salford Royal Hospital, Salford, UK.
authors.forename: Yvonne S
authors.initials: YS
authors.lastname: Davidson
authors.affiliation: Institute of Brain, Behaviour and Mental Health, University of Manchester, Salford Royal Hospital, Salford, UK.
authors.forename: David M A
authors.initials: DM
authors.lastname: Mann
mesh_terms: D000368:Aged; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D000073885:C9orf72 Protein; D042622:DNA Repeat Expansion; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004151:Dipeptides / Q000378:metabolism*; D005260:Female; D057174:Frontotemporal Lobar Degeneration / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D002479:Inclusion Bodies / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009474:Neurons / Q000378:metabolism / 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; dipeptide repeat proteins; frontotemporal lobar degeneration; hexanucleotide repeat expansion