The DOI matches its Crossref record; 69 of the 69 references it cites were found in a registry or an index.
The neuropathology associated with repeat expansions in the C9ORF72 gene
Abstract
An abnormal expansion of a GGGGCC hexanucleotide repeat in a non-coding region of the chromosome 9 open reading frame 72 gene (C9ORF72) is the most common genetic abnormality in familial and sporadic FTLD and ALS and the cause in most families where both, FTLD and ALS, are inherited. Pathologically, C9ORF72 expansion cases show a combination of FTLD-TDP and classical ALS with abnormal accumulation of TDP-43 into neuronal and oligodendroglial inclusions consistently seen in the frontal and temporal cortex, hippocampus and pyramidal motor system. In addition, a highly specific feature in C9ORF72 expansion cases is the presence of ubiquitin and p62 positive, but TDP-43 negative neuronal cytoplasmic and intranuclear inclusions. These TDP-43 negative inclusions contain dipeptide-repeat (DPR) proteins generated by unconventional repeat-associated translation of C9ORF72 transcripts with the expanded repeats and are most abundant in the cerebellum, hippocampus and all neocortex regions. Another consistent pathological feature associated with the production of C9ORF72 transcripts with expanded repeats is the formation of nuclear RNA foci that are frequently observed in the frontal cortex, hippocampus and cerebellum. Here, we summarize the complexity and heterogeneity of the neuropathology associated with the C9ORF72 expansion. We discuss implications of the data to the current classification of FTLD and critically review current insights from clinico-pathological correlative studies regarding the fundamental questions as to what processes are required and sufficient to trigger neurodegeneration in C9ORF72 disease pathogenesis.
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“In the most commonly inherited form of ALS and FTD due to mutations in the C9orf72 gene (described below), SQSTM1 accumulates together with ubiquitin in neurons and glia [119–121] as well as muscle fibers [122].”
From Autophagy and ALS: mechanistic insights and therapeutic implications (2022) · cites this paper as [120]
In the citing paper
“ALS-FTD due to C9orf72 mutations displays TARDBP pathology, consisting of granular neuronal cytoplasmic inclusions, diffuse neuronal cytoplasmic staining, and glial cytoplasmic inclusions rich in TARDBP [120].”
From Autophagy and ALS: mechanistic insights and therapeutic implications (2022) · cites this paper as [120]
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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
Self-citationDeJesus-Hernandez, M., Mackenzie, I. R., Boeve, B. F., Boxer, A. L., Baker, M., Rutherford, N. J., Nicholson, A. M., Finch, N. A., Flynn, H., Adamson, J., et al. (2011) · Neuron · doi:10.1016/j.neuron.2011.09.011 · Cited by 4,936
Self-citationA Hexanucleotide Repeat Expansion in C9ORF72 Is the Cause of Chromosome 9p21-Linked ALS-FTD
Renton, A. E., Majounie, E., Waite, A., Simón-Sánchez, J., Rollinson, S., Gibbs, J. R., Schymick, J. C., Laaksovirta, H., van Swieten, J. C., Myllykangas, L., et al. (2011) · Neuron · doi:10.1016/j.neuron.2011.09.010 · Cited by 4,409
The C9orf72 GGGGCC Repeat Is Translated into Aggregating Dipeptide-Repeat Proteins in FTLD/ALS
Mori, K., Weng, S., Arzberger, T., May, S., Rentzsch, K., Kremmer, E., Schmid, B., Kretzschmar, H. A., Cruts, M., Broeckhoven, C. V., et al. (2013) · Science · doi:10.1126/science.1232927 · Cited by 1,248
Ash, P. E. A., Bieniek, K. F., Gendron, T. F., Caulfield, T. R., Lin, W.-L., DeJesus‐Hernandez, M., van Blitterswijk, M., Jansen‐West, K. R., Paul, J. W., Rademakers, R., et al. (2013) · Neuron · doi:10.1016/j.neuron.2013.02.004 · Cited by 1,127
A harmonized classification system for FTLD-TDP pathology
Mackenzie, I. R., Neumann, M., Baborie, A., Sampathu, D. M., du Plessis, D., Jaros, E., Perry, R. H., Trojanowski, J. Q., Mann, D. M. A., & Lee, V. M. ‐. (2011) · Acta Neuropathologica · doi:10.1007/s00401-011-0845-8 · Cited by 1,042
Self-citationMackenzie, I. R. A., Neumann, M., Bigio, E. H., Cairns, N. J., Alafuzoff, I., Kril, J., Kovacs, G. G., Ghetti, B., Halliday, G., Holm, I. E., et al. (2010) · Acta Neuropathologica · doi:10.1007/s00401-009-0612-2 · Cited by 1,012
Self-citationTDP-43 and FUS in amyotrophic lateral sclerosis and frontotemporal dementia
Mackenzie, I. R., Rademakers, R., & Neumann, M. (2010) · The Lancet Neurology · doi:10.1016/s1474-4422(10)70195-2 · Cited by 1,012
Self-citationMackenzie, I. R. A., Bigio, E. H., Ince, P. G., Geser, F., Neumann, M., Cairns, N. J., Kwong, L. K., Forman, M. S., Ravits, J., Stewart, H., et al. (2007) · Annals of Neurology · doi:10.1002/ana.21147 · Cited by 992
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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Modeling C9ORF72 loss-of-function : a knockdown mouse model
Lopez-Herdoiza, M.-B. (2016) · theses.fr (ABES) · doi:10.70675/dfc77570z827az4993z840dz21dfc54360de
Unravelling the tangle of motor neuron diseases : insights from neuroimaging and neurophysiology
Querin, G. (2019) · theses.fr (ABES) · doi:10.70675/30ad3e2az5051z4364z9ec1z4b8d1f952b7b
de Calbiac, H. (2019) · theses.fr (ABES) · doi:10.70675/bafe951fz8332z4b0azb55bzac8a4af1955b
Comprendre et modéliser la Sclérose Latérale Amyotrophique à début précoce
Muratet, F. (2022) · theses.fr (ABES) · doi:10.70675/9a7778aaz88c7z40b1z92d3zaf5699b86a09
Chauhan, B. S., Brennan, M. A., Forstmeier, P. C., Han, Y., Godfrey, R. K., Keuren‐Jensen, K. R. V., Sattler, R., Ichida, J. K., & Zarnescu, D. C. (2026) · Acta Neuropathologica Communications · doi:10.64898/2026.05.08.723849
Glial cell toxicity in a Drosophila C9orf72 neurodegeneration model
Hubbard, I., & Dubnau, J. (2026) · PLoS Genetics · doi:10.1371/journal.pgen.1011909
Metadata
- Authors
- Mackenzie, I. R. A., Frick, P., & Neumann, M.
- Affiliations
- University of British Columbia (CA)
- German Center for Neurodegenerative Diseases (DE)
- Corresponding author
- Neumann, Manuela
- Venue
- Acta Neuropathologica
- Published
- 2013-12-20
- Volume
- 127
- Issue
- 3
- Pages
- 347-357
- ISSN
- 0001-6322 (ISSN-L)
- 1432-0533
- OpenAlex
- W2121553631
- Cited by
- 206
- References
- 69
- Citations by year
- 2026: 4 · 2025: 6 · 2024: 17 · 2023: 13 · 2022: 20 · 2021: 14 · 2020: 17 · 2019: 17 · 2018: 20 · 2017: 16 · 2016: 23 · 2015: 28 · 2014: 11
- FWCI
- 2.71
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Acta Neuropathologica (publishedVersion)
- PubMed (publishedVersion)
- DZNE Pub (submittedVersion)
- 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, GGGGCC repeat expansion, frontotemporal lobar degeneration, amyotrophic lateral sclerosis, TDP-43, dipeptide repeat proteins, repeat-associated non-AUG translation, ubiquitin-positive inclusions, p62, neurodegeneration, neuropathology, FTLD-TDP
- MeSH terms
- C9orf72 Protein, Brain, DNA-Binding Proteins, Humans, Phenotype, Proteins, Neurodegenerative Diseases, DNA Repeat Expansion, Frontotemporal Lobar Degeneration
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