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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.
- Source :
-
Neuropathology and applied neurobiology [Neuropathol Appl Neurobiol] 2016 Apr; Vol. 42 (3), pp. 242-54. Date of Electronic Publication: 2015 Dec 07. - Publication Year :
- 2016
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Abstract
- Aims: 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.<br />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).<br />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.<br />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.<br /> (© 2015 The Authors. Neuropathology and Applied Neurobiology published by John Wiley & Sons Ltd on behalf of British Neuropathological Society.)
- Subjects :
- Aged
C9orf72 Protein
DNA Repeat Expansion
Dipeptides
Female
Frontotemporal Lobar Degeneration genetics
Humans
Immunohistochemistry
Inclusion Bodies metabolism
Inclusion Bodies pathology
Male
Middle Aged
Motor Neuron Disease genetics
Nerve Degeneration genetics
Neurons pathology
DNA-Binding Proteins metabolism
Frontotemporal Lobar Degeneration pathology
Motor Neuron Disease pathology
Nerve Degeneration pathology
Proteins genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1365-2990
- Volume :
- 42
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Neuropathology and applied neurobiology
- Publication Type :
- Academic Journal
- Accession number :
- 26538301
- Full Text :
- https://doi.org/10.1111/nan.12292