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

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. Methods Using antibodies to poly‐GA, poly‐GP, poly‐GR,...

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Published inNeuropathology and applied neurobiology Vol. 42; no. 3; pp. 242 - 254
Main Authors 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. A.
Format Journal Article
LanguageEnglish
Published England Blackwell Publishing Ltd 01.04.2016
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John Wiley and Sons Inc
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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. 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. Abundant dipeptide repeat aggregates in regions without neurodegeneration and the sparsity of inclusions in lower motor neurons in cases with motor neuron disease support the conclusion that dipeptide repeat pathology is not the direct cause of neurodegeneration.
AbstractList 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. 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.
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. 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). 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. 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.
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. 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. Abundant dipeptide repeat aggregates in regions without neurodegeneration and the sparsity of inclusions in lower motor neurons in cases with motor neuron disease support the conclusion that dipeptide repeat pathology is not the direct cause of neurodegeneration.
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. 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. Abundant dipeptide repeat aggregates in regions without neurodegeneration and the sparsity of inclusions in lower motor neurons in cases with motor neuron disease support the conclusion that dipeptide repeat pathology is not the direct cause of neurodegeneration.
Author Mann, D. M. A.
Hamdalla, H.
Masuda-Suzukake, M.
Tian, J.
Richardson, A.
Wu, D.
Suzuki, G.
Snowden, J. S.
Liu, X.
Hasegawa, M.
Pickering-Brown, S.
Ealing, J.
Troakes, C.
Nonaka, T.
Davidson, Y.
Shi, J.
Jones, M.
Robinson, A. C.
Rollinson, S.
AuthorAffiliation 4 Clinical and Cognitive Sciences Research Group Institute of Brain, Behaviour and Mental Health Faculty of Medical and Human Sciences University of Manchester Manchester UK
7 Cerebral Function Unit Salford Royal Hospital Manchester UK
3 London Neurodegenerative Diseases Brain Bank Department of Basic and Clinical Neuroscience Institute of Psychiatry, Psychology and Neuroscience King's College London London UK
2 Beijing University of Chinese Medicine Dongzhimen Hospital Beijing China
6 Manchester MND Care Centre Salford Royal Hospital Manchester UK
1 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
5 Department of Neuropathology and Cell Biology Tokyo Metropolitan Institute of Medical Science Tokyo Japan
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BackLink https://www.ncbi.nlm.nih.gov/pubmed/26538301$$D View this record in MEDLINE/PubMed
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Copyright 2015 The Authors. published by John Wiley & Sons Ltd on behalf of British Neuropathological Society.
2015 The Authors. Neuropathology and Applied Neurobiology published by John Wiley & Sons Ltd on behalf of British Neuropathological Society.
Copyright © 2016 British Neuropathological Society
Copyright_xml – notice: 2015 The Authors. published by John Wiley & Sons Ltd on behalf of British Neuropathological Society.
– notice: 2015 The Authors. Neuropathology and Applied Neurobiology published by John Wiley & Sons Ltd on behalf of British Neuropathological Society.
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Issue 3
Keywords dipeptide repeat proteins
TDP-43
motor neurone disease
frontotemporal lobar degeneration
C9orf72
Language English
License Attribution
2015 The Authors. Neuropathology and Applied Neurobiology published by John Wiley & Sons Ltd on behalf of British Neuropathological Society.
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This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
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Medical Research Council
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Alzheimer's Society
Figure S1. Specificity of antibodies for their antigenic protein as determined by ELISA, for anti GR (A), anti GP (B) anti AP and anti PR (both C) antibodies.Figure S2. Specificity of antibodies for their antigenic protein as determined by Western blotting of proteins extracted from cell lines expressing the relevant peptide.Table S1. selected clinical, neuropathological and genetic data on the 29 cases employed in the study.Table S2. Post hoc (Mann-Whitney) significance values for comparisons between scores for DPR immunostaining using antibodies against poly-GA, poly-GP and poly-GR proteins following attainment of significant difference when comparing scores for all three antibodies by Kruskal-Wallis test. Table S3. Significance values for comparisons of scores (by Mann-Whitney test) for DPR immunostaining in different brain regions using Manchester and Tokyo poly-GP, and Manchester and Tokyo poly-GR antibodies.
Institutions of Higher Education for Academic Disciplinary Innovations - No. B08006
Alzheimer's Research UK
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PublicationTitle Neuropathology and applied neurobiology
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Snippet Aims A hexanucleotide expansion in C9orf72 is the major genetic cause of inherited behavioural variant Frontotemporal dementia (bvFTD) and motor neurone...
A hexanucleotide expansion in C9orf72 is the major genetic cause of inherited behavioural variant Frontotemporal dementia (bvFTD) and motor neurone disease...
Aims A hexanucleotide expansion in C9orf72 is the major genetic cause of inherited behavioural variant Frontotemporal dementia (bvFTD) and motor neurone...
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SubjectTerms Aged
C9orf72
C9orf72 Protein
dipeptide repeat proteins
Dipeptides
DNA Repeat Expansion
DNA-Binding Proteins - metabolism
Female
frontotemporal lobar degeneration
Frontotemporal Lobar Degeneration - genetics
Frontotemporal Lobar Degeneration - pathology
Humans
Immunohistochemistry
Inclusion Bodies - metabolism
Inclusion Bodies - pathology
Male
Middle Aged
Motor Neuron Disease - genetics
Motor Neuron Disease - pathology
motor neurone disease
Nerve Degeneration - genetics
Nerve Degeneration - pathology
Neurons - pathology
Original
Pathology
Proteins
Proteins - genetics
Spinal cord
TDP-43
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
URI https://api.istex.fr/ark:/67375/WNG-Q3Z3KPWN-9/fulltext.pdf
https://onlinelibrary.wiley.com/doi/abs/10.1111%2Fnan.12292
https://www.ncbi.nlm.nih.gov/pubmed/26538301
https://www.proquest.com/docview/1776710579
https://search.proquest.com/docview/1780524298
https://pubmed.ncbi.nlm.nih.gov/PMC4832296
Volume 42
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