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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
Review

Abstract

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.

Keywords

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 

Abbreviations

ADARB2

Adenosine deaminase RNA-specific B2

ALS

Amyotrophic lateral sclerosis

ATG

Adenine–thymine–guanine (start codon)

C9+

G4C2 repeat-expanded C9ORF72 allele

C9ORF72

Chromosome 9 open reading frame 72

CBLN1

Cerebellin 1 precursor protein

CBLN2

Cerebellin 2 precursor protein

CBLN4

Cerebellin 4 precursor protein

CHRDL1

Chordin-like 1

CP

Ceruloplasmin

CpG

Cytosine-phosphate–guanine

DENN

Differentially expressed in normal and neoplastic cells

DM1

Myotonic dystrophy type 1

DM2

Myotonic dystrophy type 2

DMPK

Dystrophia myotonica-protein kinase

DNA

Deoxyribonucleic acid

DPP6

Dipeptidyl aminopeptidase-like protein 6

DPR

Dipeptide-repeat protein

EDN1

Endothelin 1

EGFP

Enhanced green fluorescent protein

FAM3C

Family with sequence similarity 3, member C

FISH

Fluorescent in situ hybridisation

FTD

Frontotemporal dementia

FTLD

Frontotemporal lobar degeneration

FMR1

Fragile-X mental retardation 1

FMRP

Fragile-X mental retardation protein

FUS

Fused-in-sarcoma

FXS

Fragile-X syndrome

FXTAS

Fragile-X tremor/ataxia syndrome

GA

Glycine–alanine

GP

Glycine–proline

GR

Glycine–arginine

G-quadruplex

Guanine-quadruplex

G4C2

Guanine4cytosine2

GEF

Guanine-diphosphate/guanine-triphosphate exchange factor

GWAS

Genome-wide association study

HEK293

Human embryonic kidney 293 cells

hnRNP

Heterogenous nuclear ribonucleoprotein

iPSC

Induced pluripotent stem cell

iPSN

Induced pluripotent stem cell-differentiated neuron

KCNQ3

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

mRNA

Messenger RNA

NEDD4L

E3 ubiquitin-protein ligase NEDD4-like

PA

Proline alanine

PARP

Polyadenosine diphosphate-ribose polymerase

PR

Proline arginine

RAN translation

Repeat-associated non-ATG translation

RNA

Ribonucleic acid

RBP

RNA-binding protein

SC35

Serine/arginine-rich splicing factor 2

SEPP

Selenoprotein P, plasma, 1

SERPINE2

Serpin peptidase inhibitor, clade E, member 2

SF2

Serine/arginine-rich splicing factor 1

siRNA

Small interfering RNA

TARBP2

Transactive response RNA-binding protein 2

TDP-43

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

Trem2

Triggering receptor expressed on myeloid cells 2

TUNEL

Terminal deoxynucleotidyl transferase dUTP nick end labelling

UTR

Untranslated region

V1

Variant 1

V2

Variant 2

V3

Variant 3

ZNF9

Zinc finger 9

Notes

Acknowledgments

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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