Acta Neuropathologica

, Volume 127, Issue 3, pp 377–389 | Cite as

Modelling C9ORF72 hexanucleotide repeat expansion in amyotrophic lateral sclerosis and frontotemporal dementia

  • Alan Stepto
  • Jean-Marc Gallo
  • Christopher E. Shaw
  • Frank HirthEmail author


GGGGCC (G4C2) hexanucleotide repeat expansion in chromosome 9 open reading frame 72 (C9ORF72) has been identified as the most common genetic abnormality in both frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). To investigate the role of C9ORF72-related G4C2 repeat expansion in ALS and FTLD, several animal and cell culture models have been generated that reveal initial insights into the disease pathogenesis of C9 ALS/FTLD. These models include neurons differentiated from patient-derived pluripotent stem cells as well as genetically engineered cells and organisms that knock down C9ORF72 orthologues or express G4C2 repeats. Targeted reduction or knockdown of C9ORF72 homologues in zebrafish and mice so far produced conflicting results which neither rule out, nor confirm reduced expression of C9ORF72 as a pathogenic mechanism in C9 ALS/FTLD. In contrast, studies using patient-derived cells, as well as Drosophila and zebrafish models overexpressing disease-related hexanucleotide expansions, can cause repeat length-dependent formation of RNA foci, which directly and progressively correlate with cellular toxicity. RNA foci formation is accompanied by sequestration of specific RNA-binding proteins (RBPs), including Pur-alpha, hnRNPH and ADARB2, suggesting that G4C2-mediated sequestration and functional depletion of RBPs are cytotoxic and thus directly contribute to disease. Moreover, these studies provide experimental evidence that repeat-associated non-ATG translation of repeat-containing sense and antisense RNA leads to dipeptide-repeat proteins (DPRs) that can accumulate and aggregate, indicating that accumulation of DPRs may represent another pathogenic pathway underlying C9 ALS/FTLD. These studies in cell and animal models therefore identify RNA toxicity, RBP sequestration and accumulation of DPRs as emerging pathogenic pathways underlying C9 ALS/FTLD.


GGGGCC (G4C2) hexanucleotide repeat expansion Chromosome 9 open reading frame 72 (C9ORF72Frontotemporal dementia (FTD) Frontotemporal lobar degeneration (FTLD) Amyotrophic lateral sclerosis (ALS) Induced pluripotent stem cells (iPSCs) Drosophila Zebrafish Mouse RNA foci RNA toxicity hnRNP RBP TDP-43 Sequestration Repeat associated non-ATG (RAN) translation Dipeptide-repeat protein (DPR) Repeat-associated neurodegenerative disease 



Adenosine deaminase RNA-specific B2


Amyotrophic lateral sclerosis


Adenine–thymine–guanine (start codon)


G4C2 repeat-expanded C9ORF72 allele


Chromosome 9 open reading frame 72


Cerebellin 1 precursor protein


Cerebellin 2 precursor protein


Cerebellin 4 precursor protein


Chordin-like 1






Differentially expressed in normal and neoplastic cells


Myotonic dystrophy type 1


Myotonic dystrophy type 2


Dystrophia myotonica-protein kinase


Deoxyribonucleic acid


Dipeptidyl aminopeptidase-like protein 6


Dipeptide-repeat protein


Endothelin 1


Enhanced green fluorescent protein


Family with sequence similarity 3, member C


Fluorescent in situ hybridisation


Frontotemporal dementia


Frontotemporal lobar degeneration


Fragile-X mental retardation 1


Fragile-X mental retardation protein




Fragile-X syndrome


Fragile-X tremor/ataxia syndrome












Guanine-diphosphate/guanine-triphosphate exchange factor


Genome-wide association study


Human embryonic kidney 293 cells


Heterogenous nuclear ribonucleoprotein


Induced pluripotent stem cell


Induced pluripotent stem cell-differentiated neuron


Potassium voltage-gated channel, KQT-like subfamily, member 3


Messenger RNA


E3 ubiquitin-protein ligase NEDD4-like


Proline alanine


Polyadenosine diphosphate-ribose polymerase


Proline arginine

RAN translation

Repeat-associated non-ATG translation


Ribonucleic acid


RNA-binding protein


Serine/arginine-rich splicing factor 2


Selenoprotein P, plasma, 1


Serpin peptidase inhibitor, clade E, member 2


Serine/arginine-rich splicing factor 1


Small interfering RNA


Transactive response RNA-binding protein 2


Transactive response DNA-binding protein with molecular weight of 43 kDa


Triggering receptor expressed on myeloid cells 2


Terminal deoxynucleotidyl transferase dUTP nick end labelling


Untranslated region


Variant 1


Variant 2


Variant 3


Zinc finger 9



We thank Michael Niblock for critical reading of the manuscript. Work in the Shaw, Gallo and Hirth laboratories are funded by a Strategic Grant Award from The Wellcome Trust and Medical Research Council (MRC) (089701), the Motor Neuron Disease Association (Hirth/3/400 and Hirth/Mar12/6085), the American ALS Association (to C.E.S.), Heaton-Ellis Trust (to C.E.S.), MRC grants (G0900688 to C.E.S. and MR/L010666/1 to F.H.), the National Institutes of Health Research Biomedical Research Centre for Mental Health at the South London and Maudsley National Health Service Foundation Trust, the Psychiatry Research Trust, the European Community’s Seventh Framework Programme (FP7/2007–2013) under the grant agreement number 259867, Alzheimer’s Research UK (Hirth/ARUK/2012) and the Fondation Thierry Latran (DrosALS) (to F.H.).


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Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Alan Stepto
    • 1
  • Jean-Marc Gallo
    • 2
  • Christopher E. Shaw
    • 2
  • Frank Hirth
    • 1
    Email author
  1. 1.Department of Neuroscience, Institute of PsychiatryKing’s College LondonLondonUK
  2. 2.Department of Clinical Neuroscience, Institute of PsychiatryKing’s College LondonLondonUK

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