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Accumulation of dipeptide repeat proteins predates that of TDP-43 in frontotemporal lobar degeneration associated with hexanucleotide repeat expansions in C9ORF72 gene

Lookup NU author(s): Professor Tim GriffithsORCiD, Dr Evelyn Jaros, Emeritus Professor Robert Perry, Professor Ian McKeith, Professor David Burn


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AimsFrontotemporal 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.MethodsTwenty-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.ResultsThree 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.ConclusionWidespread accumulation of DPR within nerve cells may occur much earlier than that of TDP-43 in patients with FTLD bearing expansion in C9ORF72.

Publication metadata

Author(s): Baborie A, Griffiths TD, Jaros E, Perry R, McKeith IG, Burn DJ, Masuda-Suzukake M, Hasegawa M, Rollinson S, Pickering-Brown S, Robinson AC, Davidson YS, Mann DMA

Publication type: Article

Publication status: Published

Journal: Neuropathology and Applied Neurobiology

Year: 2015

Volume: 41

Issue: 5

Pages: 601-612

Print publication date: 01/08/2015

Online publication date: 30/04/2015

Acceptance date: 14/08/2014

ISSN (print): 0305-1846

ISSN (electronic): 1365-2990

Publisher: Wiley-Blackwell Publishing Ltd.


DOI: 10.1111/nan.12178


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Funder referenceFunder name
UK NIHR Biomedical Research Centre for Ageing and Age-Related Disease
Alzheimer's Research UK, as part of the Brains for Dementia Research Project
Alzheimer's Society
Newcastle NIHR Biomedical Research Centre in Ageing and Age Related Diseases award
Wellcome Trust
G1100540UK Medical Research Council
G0400074UK Medical Research Council