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Dipeptide repeat protein pathology in C9ORF72 mutation cases: clinico-pathological correlations
Open accessAbstract
Hexanucleotide repeat expansion in C9ORF72 is the most common genetic cause of frontotemporal dementia and motor neuron disease. Recently, unconventional non-ATG translation of the expanded hexanucleotide repeat, resulting in the production and aggregation of dipeptide repeat (DPR) proteins (poly-GA, -GR and GP), was identified as a potential pathomechanism of C9ORF72 mutations. Besides accumulation of DPR proteins, the second neuropathological hallmark lesion in C9ORF72 mutation cases is the accumulation of TDP-43. In this study, we characterized novel monoclonal antibodies against poly-GA and performed a detailed analysis of the neuroanatomical distribution of DPR and TDP-43 pathology in a cohort of 35 cases with the C9ORF72 mutation that included a broad spectrum of clinical phenotypes. We found the pattern of DPR pathology to be highly consistent among cases regardless of the phenotype with high DPR load in the cerebellum, all neocortical regions (frontal, motor cortex and occipital) and hippocampus, moderate pathology in subcortical areas and minimal pathology in lower motor neurons. No correlation between DPR pathology and the degree of neurodegeneration was observed, while a good association between TDP-43 pathology with clinical phenotype and degeneration in key anatomical regions was present. Our data confirm that the presence of DPR pathology is intimately related to C9ORF72 mutations. The observed dissociation between DPR inclusion body load and neurodegeneration might suggest inclusion body formation as a potentially protective response to cope with soluble toxic DPR species. Moreover, our data imply that alterations due to the C9ORF72 mutation resulting in TDP-43 accumulation and dysmetabolism as secondary downstream effects likely play a central role in the neurodegenerative process in C9ORF72 pathogenesis.
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“Antibodies specific for each dipeptide repeat (DPR) also stain SQSTM1-positive inclusions, including the star-like inclusions unique to C9orf72-related disease, suggesting that DPRs are targeted for clearance by the UPS and/or autophagy [119,169–171] (Figure 1).”
From Autophagy and ALS: mechanistic insights and therapeutic implications (2022) · cites this paper as [169]
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Ubiquitinated TDP-43 in Frontotemporal Lobar Degeneration and Amyotrophic Lateral Sclerosis
Neumann, M., Sampathu, D. M., Kwong, L. K., Truax, A. C., Micsenyi, M. C., Chou, T. T., Bruce, J., Schuck, T., Grossman, M., Clark, C. M., et al. (2006) · Science · doi:10.1126/science.1134108 · Cited by 6,576
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“The number of hexanucleotide repeats in the normal population ranges from 2 to 24 [13, 14, 17, 31, 39], whereas up to several thousand repeats (range 700–4,400 repeats) are described in the pathologically expanded allele as estimated by Southern blot analysis [5, 13, 14].”
BackgroundMethodInfluentialSelf-citationA Hexanucleotide Repeat Expansion in C9ORF72 Is the Cause of Chromosome 9p21-Linked ALS-FTD
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“Based on the observations that there is sometimes only poor correlation between the neuropathological hallmark lesions seen with neurodegeneration or phenotype, with the most prominent examples perhaps being the rather poor association of amyloid beta load with cognitive impairments [27] and intranuclear inclusions in…”
BackgroundSelf-citationInclusion body formation reduces levels of mutant huntingtin and the risk of neuronal death
Arrasate, M., Mitra, S., Schweitzer, E. S., Segal, M. R., & Finkbeiner, S. (2004) · Nature · doi:10.1038/nature02998 · Cited by 1,979
The C9orf72 GGGGCC Repeat Is Translated into Aggregating Dipeptide-Repeat Proteins in FTLD/ALS
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A harmonized classification system for FTLD-TDP pathology
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Self-citationNon-ATG–initiated translation directed by microsatellite expansions
Zu, T., Gibbens, B. B., Doty, N. S., Gomes-Pereira, M., Huguet-Lachon, A., Stone, M. D., Margolis, J., Peterson, M., Markowski, T. W., Ingram, M. A. C., et al. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1013343108 · Cited by 928
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Taylor, J. P., Brown, R. H., & Cleveland, D. W. (2016) · Nature · doi:10.1038/nature20413 · Cited by 2,120
C9orf72 repeat expansions cause neurodegeneration in Drosophila through arginine-rich proteins
Mizielinska, S., Grönke, S., Niccoli, T., Ridler, C. E., Clayton, E. L., Devoy, A., Moens, T., Norona, F. E., Woollacott, I. O. C., Pietrzyk, J., et al. (2014) · Science · doi:10.1126/science.1256800 · Cited by 740
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Balendra, R., & Isaacs, A. M. (2018) · Nature Reviews Neurology · doi:10.1038/s41582-018-0047-2 · Cited by 715
RNA Binding Antagonizes Neurotoxic Phase Transitions of TDP-43
Mann, J. R., Gleixner, A. M., Mauna, J. C., Gomes, E., DeChellis-Marks, M. R., Needham, P. G., Copley, K. E., Hurtle, B. T., Portz, B., Pyles, N. J., et al. (2019) · Neuron · doi:10.1016/j.neuron.2019.01.048 · Cited by 547
Cooper‐Knock, J., Bury, J. J., Heath, P. R., Wyles, M., Higginbottom, A., Gelsthorpe, C., Highley, J. R., Hautbergue, G. M., Rattray, M., Kirby, J., et al. (2015) · PLoS ONE · doi:10.1371/journal.pone.0127376 · Cited by 521
Metadata
- Authors
- Mackenzie, I. R., Arzberger, T., Kremmer, E., Troost, D., Lorenzl, S., Mori, K., Weng, S.-M., Haass, C., Kretzschmar, H. A., Edbauer, D., & Neumann, M.
- Affiliations
- University of British Columbia (CA)
- German Center for Neurodegenerative Diseases (DE)
- Amsterdam UMC Location University of Amsterdam (NL)
- Ludwig-Maximilians-Universität München (DE)
- Adolf-Butenandt-Institut für Physiologische Chemie, Physikalische Biochemie und Zellbiologie (DE)
- Institut für Neuropathologie (DE)
- Corresponding author
- Edbauer, Dieter
- Neumann, Manuela
- Venue
- Acta Neuropathologica
- Published
- 2013-10-06
- Volume
- 126
- Issue
- 6
- Pages
- 859-879
- ISSN
- 0001-6322 (ISSN-L)
- 1432-0533
- OpenAlex
- W2092145129
- Cited by
- 345
- References
- 41
- Citations by year
- 2026: 8 · 2025: 17 · 2024: 17 · 2023: 19 · 2022: 16 · 2021: 31 · 2020: 31 · 2019: 36 · 2018: 36 · 2017: 43 · 2016: 26 · 2015: 34 · 2014: 29 · 2013: 2
- FWCI
- 19.25
- Type
- journal article
- Language
- en
- Open access
- green
- hdl.handle.net
- Licence
- cc-by-nc-nd
- www.springer.com/tdm (tdm)
- Locations
- Acta Neuropathologica (publishedVersion)
- PubMed (publishedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- cIRcle (University of British Columbia) (submittedVersion, cc-by-nc-nd)
- Site cant be reached (submittedVersion)
- DZNE Pub (submittedVersion)
- Pure Amsterdam UMC (submittedVersion)
- Open Collections
- Funders
- Canadian Institutes of Health Research (74580)
- Topics
- Health Sciences › Medicine › Clinical Neurology › Amyotrophic Lateral Sclerosis Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Keywords
- C9orf72 mutation, dipeptide repeat proteins, hexanucleotide repeat expansion, TDP-43 pathology, frontotemporal dementia, motor neuron disease, monoclonal antibodies, neurodegeneration, cerebellum, hippocampus, motor cortex, lower motor neurons, inclusion bodies, neuropathology
- MeSH terms
- C9orf72 Protein, Adult, Aged, Amyotrophic Lateral Sclerosis, Brain, DNA-Binding Proteins, Humans, Middle Aged, Mutation, Proteins, DNA Repeat Expansion, Frontotemporal Dementia
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