The DOI matches its Crossref record; 223 of the 223 references it cites were found in a registry or an index.
C9orf72-mediated ALS and FTD: multiple pathways to disease
Open accessAbstract
The discovery that repeat expansions in the C9orf72 gene are a frequent cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) has revolutionized our understanding of these diseases. Substantial headway has been made in characterizing C9orf72-mediated disease and unravelling its underlying aetiopathogenesis. Three main disease mechanisms have been proposed: loss of function of the C9orf72 protein and toxic gain of function from C9orf72 repeat RNA or from dipeptide repeat proteins produced by repeat-associated non-ATG translation. Several downstream processes across a range of cellular functions have also been implicated. In this article, we review the pathological and mechanistic features of C9orf72-associated FTD and ALS (collectively termed C9FTD/ALS), the model systems used to study these conditions, and the probable initiators of downstream disease mechanisms. We suggest that a combination of upstream mechanisms involving both loss and gain of function and downstream cellular pathways involving both cell-autonomous and non-cell-autonomous effects contributes to disease progression.
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“Experimental results support toxicity of RNAs containing the expanded repeat, as well as toxicity of dipeptide repeat translated from these RNAs, but also to haploinsufficiency of the C9orf72 protein as a cause of disease6.”
From CRISPR-based functional genomics for neurological disease (2020) · cites this paper as [6]
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Metadata
- Authors
- Balendra, R., & Isaacs, A. M.
- Affiliations
- UCL Queen Square Institute of Neurology (GB)
- UK Dementia Research Institute (GB)
- Corresponding author
- Isaacs, Adrian M.
- Venue
- Nature Reviews Neurology
- Published
- 2018-08-17
- Volume
- 14
- Issue
- 9
- Pages
- 544-558
- ISSN
- 1759-4758 (ISSN-L)
- 1759-4766
- PMC
- PMC6417666
- OpenAlex
- W2887838825
- Cited by
- 715
- References
- 223
- Citations by year
- 2026: 62 · 2025: 84 · 2024: 98 · 2023: 109 · 2022: 89 · 2021: 116 · 2020: 99 · 2019: 48 · 2018: 8
- FWCI
- 10.71
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Reviews Neurology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Funders
- Wellcome Trust (107196, 107196/Z/14/Z)
- National Institute for Health and Care Research (ACF-2011-17-018)
- Motor Neurone Disease Association (ISAACS/APR15/834-791)
- 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, amyotrophic lateral sclerosis, frontotemporal dementia, repeat expansion, loss of function, gain-of-function, dipeptide repeat proteins, repeat-associated non-ATG translation, disease mechanisms, model systems
- MeSH terms
- C9orf72 Protein, Amyotrophic Lateral Sclerosis, Animals, Disease Models, Animal, Humans, Frontotemporal Dementia
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