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C9orf72-mediated ALS and FTD: multiple pathways to disease

Balendra, R; Isaacs, AM; (2018) C9orf72-mediated ALS and FTD: multiple pathways to disease. Nature Reviews Neurology , 14 (9) pp. 544-558. 10.1038/s41582-018-0047-2. Green open access

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Abstract

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.

Type: Article
Title: C9orf72-mediated ALS and FTD: multiple pathways to disease
Open access status: An open access version is available from UCL Discovery
DOI: 10.1038/s41582-018-0047-2
Publisher version: http://dx.doi.org/10.1038/s41582-018-0047-2
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: Science & Technology, Life Sciences & Biomedicine, Clinical Neurology, Neurosciences & Neurology, AMYOTROPHIC-LATERAL-SCLEROSIS, DIPEPTIDE-REPEAT PROTEINS, FRONTOTEMPORAL LOBAR DEGENERATION, C9ORF72 HEXANUCLEOTIDE REPEAT, STRESS GRANULE FORMATION, G-QUADRUPLEX STRUCTURES, RNA-BINDING PROTEINS, BAC TRANSGENIC MICE, MOUSE MODEL, NUCLEOCYTOPLASMIC TRANSPORT
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Neurodegenerative Diseases
URI: https://discovery.ucl.ac.uk/id/eprint/10058232
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