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C9orf72-mediated ALS and FTD: multiple pathways to disease

Nature Reviews Neurologyvolume 14pages544558 (2018) | Download Citation


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.

Key points

  • Rapid progress has been made in the understanding of how repeat expansions in C9orf72 cause C9orf72-associated frontotemporal dementia and/or amyotrophic lateral sclerosis (C9FTD/ALS).

  • Both loss of function of C9orf72 and gain of toxic function of the repeats are implicated in C9FTD/ALS.

  • A range of new models, including mice, Drosophila and patient neurons, have provided new insights into the disease mechanisms.

  • Several cellular pathways are affected in C9FTD/ALS and could provide new options for treatment.

  • Targeted therapeutic strategies against the repeats themselves are the most advanced and are progressing towards clinical trials.

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R.B. is a Leonard Wolfson Clinical Research Training Fellow and is funded by a Wellcome Trust Research Training Fellowship (107196/Z/14/Z). A.M.I. is funded by the Motor Neuron Disease Association, Alzheimer’s Research UK, the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (648716 — C9ND) and the UK Dementia Research Institute. The authors thank S. Mizielinska for reviewing the manuscript and assistance with figures and M. Guadalupi and R. Saccon for assistance with and design of figures.

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Nature Reviews Neurology thanks P. Shaw and the other anonymous reviewers for their contribution to the peer review of this work.

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  1. Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK

    • Rubika Balendra
    •  & Adrian M. Isaacs
  2. Department of Genetics, Evolution and Environment, Institute of Healthy Ageing, UCL, London, UK

    • Rubika Balendra
  3. UK Dementia Research Institute at UCL, UCL Institute of Neurology, London, UK

    • Adrian M. Isaacs


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Both authors researched data for the article, discussed the content, wrote the article and reviewed and edited the manuscript before submission.

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The authors declare no competing interests.

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Correspondence to Adrian M. Isaacs.

Supplementary information


Repeat-associated non-ATG (RAN) translation

Translation is canonically dependent on an ATG start codon for initiation. RAN translation is a non-canonical form of translation that, in the presence of repetitive sequences, can start without the need for an ATG codon.


Secondary structures in which an RNA or DNA molecule folds back onto itself to resemble a hairpin.


Secondary structures formed by guanine-rich RNA or DNA molecules consisting of a stack of G-quartets (four guanine residues aligned in a square planar configuration).


Four-stranded secondary structures formed by cytosine-rich DNA or RNA molecules.

Frontotemporal lobar degeneration

(FTLD). A term describing the pathological findings observed in patients with frontotemporal dementia (FTD); however, FTLD and FTD are also often used interchangeably to describe the clinical syndrome.

Cryo-electron tomography

A high-resolution technique that involves collecting a series of tilted images of frozen hydrated samples using an electron microscope to produce a 3D reconstruction of the sample.

Bacterial artificial chromosome

(BAC). A vector for maintaining large pieces of DNA, often 50–200 kb in size.


Processing bodies, or P-bodies, are membrane-less organelles within the cytoplasm that are involved in translational repression of mRNAs and in mRNA silencing and degradation.

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