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Cellular and Molecular Life Sciences

, Volume 73, Issue 21, pp 4085–4100 | Cite as

Modeling simple repeat expansion diseases with iPSC technology

  • Edyta Jaworska
  • Emilia Kozlowska
  • Pawel M. Switonski
  • Wlodzimierz J. KrzyzosiakEmail author
Review

Abstract

A number of human genetic disorders, including Huntington’s disease, myotonic dystrophy type 1, C9ORF72 form of amyotrophic lateral sclerosis and several spinocerebellar ataxias, are caused by the expansion of various microsatellite sequences in single implicated genes. The neurodegenerative and neuromuscular nature of the repeat expansion disorders considerably limits the access of researchers to appropriate cellular models of these diseases. This limitation, however, can be overcome by the application of induced pluripotent stem cell (iPSC) technology. In this paper, we review the current knowledge on the modeling of repeat expansion diseases with human iPSCs and iPSC-derived cells, focusing on the disease phenotypes recapitulated in these models. In subsequent sections, we provide basic practical knowledge regarding iPSC generation, characterization and differentiation into neurons. We also cover disease modeling in iPSCs, neuronal stem cells and specialized neuronal cultures. Furthermore, we also summarize the therapeutic potential of iPSC technology in repeat expansion diseases.

Keywords

Pluripotent cells TRED PolyQ diseases Triplet repeat expansion Neurodegeneration Neurons 

Abbreviations

17-AAG

17-Allylaminogeldanamycin

3-MA

3-Methyladenine

ALS

Amyotrophic lateral sclerosis

AR

Androgen receptor

ATM

Ataxia-telangiectasia mutated protein

ATXN3

Ataxin-3

BDNF

Brain-derived neurotrophic factor

CNS

Central nervous system

CRISPR/Cas9

Clustered, regularly interspaced, short, palindromic repeats/Cas9 system

DARPP-32

Dopamine- and cAMP-regulated phosphoprotein

DHT

Dihydrotestosterone

DKK-1

Dickopff-1

DM1

Myotonic dystrophy type 1

DRP1

Dynamin-related protein 1

DRPLA

Dentatorubral-pallidoluysian atrophy

EB

Embryoid body

EGF

Epidermal growth factor

ERK

Extracellular signal-regulated kinase

ESC

Embryonic stem cell

FECD

Fuchs endothelial corneal dystrophy

FGF

Fibroblast growth factor

FMR1

Fragile X mental retardation 1

FTD

Frontotemporal dementia

FXN

Frataxin

FXS

Fragile X syndrome

FXTAS

Fragile X associated tremor/ataxia syndrome

GABA

Gamma-aminobutyric acid

HB9

Homeobox 9

HD

Huntington’s disease

HDAC

Histone deacetylase

HTT

Huntingtin

ICF

Immunocytofluorescence

iPSC

Induced pluripotent stem cell

KLF4

Krüppel-like factor 4

MAP-2

Microtubule-associated protein 2

MAPK

Mitogen-activated protein kinase

MMR

Mismatch repair system

MSH

MutS homolog

MSN

Medium spiny neuron

NSC

Neural stem cell

OCT4

Octamer-binding protein 4

ORF

Open reading frame

PAS

PolyA signals

PKA

Protein kinase cAMP

polyQ

Polyglutamine

qPCR

Quantitative PCR

RAN

Repeat associated non-AUG translation

RBP

RNA binding protein

SBMA

Spinobulbar muscular atrophy

SCA

Spinocerebellar ataxia

SHH

Sonic hedgehog

SOD1

Superoxide dismutase 1

SOX2

Sex-determining region Y-box 2

SSEA

Stage-specific embryonic antigen

TALEN

Transcription activator-like effector nuclease

UTR

Untranslated region

ZFN

Zinc finger nuclease

Notes

Acknowledgments

This work was supported by a Grant from National Science Center (2012/06/A/NZ1/00094 to Wlodzimierz J. Krzyzosiak) and by the Polish Ministry of Science and Higher Education, under the KNOW program.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflicts of interest.

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Copyright information

© Springer International Publishing 2016

Authors and Affiliations

  1. 1.Department of Molecular Biomedicine, Institute of Bioorganic ChemistryPolish Academy of SciencesPoznanPoland

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