Cited by 208Amyotrophic Lateral Sclerosis ResearchGenetic Neurodegenerative DiseasesAlzheimer's disease research and treatments

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The neuropathology associated with repeat expansions in the C9ORF72 gene

Mackenzie, Ian R. A., Frick, Petra, Neumann, Manuela·2014·Acta Neuropathologica

DOI 10.1007/s00401-013-1232-4

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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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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
ORCID: Mackenzie, Ian R. A.
Neumann, Manuela
Venue: Acta Neuropathologica
Publisher: Springer Science and Business Media LLC
Published: 2013-12-20
Volume: 127
Issue: 3
Pages: 347-357
ISSN: 0001-6322 (ISSN-L)
1432-0533
DOI: 10.1007/s00401-013-1232-4
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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The neuropathology associated with repeat expansions in the C9ORF72 gene

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