Journal
NATURE REVIEWS NEUROLOGY
Volume 14, Issue 9, Pages 544-558Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41582-018-0047-2
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Funding
- Wellcome Trust [107196/Z/14/Z]
- Motor Neuron Disease Association
- Alzheimer's Research UK
- European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme [648716 - C9ND]
- UK Dementia Research Institute
- MRC [UKDRI-1006] Funding Source: UKRI
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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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