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
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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.
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DPR inclusions rarely co-label with TARDBP pathological inclusions and are mainly found in areas of the CNS that are not pathologically affected, arguing against a direct role for DPRs in neurodegeneration.
“On the other hand, DPR inclusions rarely co-label with TARDBP pathological inclusions and are mainly found in areas of the CNS that are not pathologically affected [171,174–177], arguing against a direct role for DPRs in neurodegeneration.”
From Autophagy and ALS: mechanistic insights and therapeutic implications (2022) · cites this paper as [174]
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- 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.
- Affiliations
- University of Manchester (GB)
- Beijing University of Chinese Medicine (CN)
- King's College London (GB)
- Tokyo Metropolitan Institute of Medical Science (JP)
- Salford Royal Hospital (GB)
- Clinical and Cognitive Sciences Research Group Institute of Brain, Behaviour and Mental Health Faculty of Medical and Human Sciences University of Manchester Manchester UK
- Corresponding author
- Mann, D. M. A.
- ORCID
- Venue
- Neuropathology and Applied Neurobiology
- Publisher
- Wiley
- Published
- 2015-12-07
- Volume
- 42
- Issue
- 3
- Pages
- 242-254
- ISSN
- 0305-1846 (ISSN-L)
- 1365-2990
- PMC
- PMC4832296
- OpenAlex
- W1893585873
- Cited by
- 77
- References
- 34
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 3 · 2023: 9 · 2022: 3 · 2021: 5 · 2020: 9 · 2019: 8 · 2018: 15 · 2017: 10 · 2016: 9 · 2015: 2
- FWCI
- 8.46
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Neuropathology and Applied Neurobiology (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Research Explorer (The University of Manchester) (publishedVersion)
- Funders
- Alzheimer’s Research UK
- Alzheimer's Society
- Medical Research Council
- Wellcome Trust (089701/Z/09/Z)
- Topics
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Keywords
- C9orf72 repeat expansion, frontotemporal lobar degeneration, motor neuron disease, dipeptide repeat proteins, TDP-43, anterior horn motor neurons, dentate gyrus, Purkinje cells, disease mechanisms
- MeSH terms
- C9orf72 Protein, Aged, Inclusion Bodies, Dipeptides, DNA-Binding Proteins, Female, Humans, Immunohistochemistry, Male, Middle Aged, Nerve Degeneration, Neurons, Proteins, Motor Neuron Disease, DNA Repeat Expansion, Frontotemporal Lobar Degeneration
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