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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
Davidson, Y; Robinson, A C; Liu, X; Wu, D; Troakes, C; Rollinson, S; Masuda-Suzukake, M; Suzuki, G; Nonaka, T; Shi, J; Tian, J; Hamdalla, H; Ealing, J; Richardson, A; Jones, M; Pickering-Brown, S; Snowden, J S; Hasegawa, M; Mann, D M
Neuropathol Appl Neurobiol. 2015;.
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Abstract
AIMS: A hexanucleotide expansion in C9orf72 is the major genetic cause of inherited Frontotemporal dementia (bvFTD), and Motor Neurone disease (MND), though 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. CONCLUSION: 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. This article is protected by copyright. All rights reserved.
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- Related website http://www.ncbi.nlm.nih.gov/pubmed/26538301
- Davidson, Yvonne Robinson, Andrew C Liu, Xiawei Wu, Dongyue Troakes, Claire Rollinson, Sara Masuda-Suzukake, Masami Suzuki, Genjiro Nonaka, Takashi Shi, Jing Tian, Jinzhou Hamdalla, Hisham Ealing, John Richardson, Anna Jones, Matthew Pickering-Brown, Stuart Snowden, Julie S Hasegawa, Masato Mann, David M A Neuropathol Appl Neurobiol. 2015 Nov 5. doi: 10.1111/nan.12292.