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Modeling simple repeat expansion diseases with iPSC technology

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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.

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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

References

  1. Mirkin SM (2007) Expandable DNA repeats and human disease. Nature 447:932–940. doi:10.1038/nature05977

    Article  CAS  PubMed  Google Scholar 

  2. Orr HT, Zoghbi HY (2007) Trinucleotide repeat disorders. Annu Rev Neurosci 30:575–621

    Article  CAS  PubMed  Google Scholar 

  3. Williams AJ, Paulson HL (2008) Polyglutamine neurodegeneration: protein misfolding revisited. Trends Neurosci 31:521–528. doi:10.1016/j.tins.2008.07.004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Fiszer A, Krzyzosiak WJ (2013) RNA toxicity in polyglutamine disorders: concepts, models, and progress of research. J Mol Med 91(6):683–691

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Chan HY (2014) RNA-mediated pathogenic mechanisms in polyglutamine diseases and amyotrophic lateral sclerosis. Front Cell Neurosci 8:431. doi:10.3389/fncel.2014.00431

    Article  PubMed  PubMed Central  Google Scholar 

  6. Nalavade R, Griesche N, Ryan DP, Hildebrand S, Krauss S (2013) Mechanisms of RNA-induced toxicity in CAG repeat disorders. Cell Death Dis 4:e752. doi:10.1038/cddis.2013.276

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Wieben ED, Aleff RA, Tosakulwong N, Butz ML, Highsmith WE, Edwards AO, Baratz KH (2012) A common trinucleotide repeat expansion within the transcription factor 4 (TCF4, E2-2) gene predicts Fuchs corneal dystrophy. PLoS One 7:e49083. doi:10.1371/journal.pone.0049083

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Miller JW, Urbinati CR, Teng-Umnuay P, Stenberg MG, Byrne BJ, Thornton CA, Swanson MS (2000) Recruitment of human muscleblind proteins to (CUG)(n) expansions associated with myotonic dystrophy. EMBO J 19(17):4439–4448. doi:10.1093/emboj/19.17.4439

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Mohan A, Goodwin M, Swanson MS (2014) RNA–protein interactions in unstable microsatellite diseases. Brain Res 1584:3–14. doi:10.1016/j.brainres.2014.03.039

    Article  CAS  PubMed  Google Scholar 

  10. Echeverria GV, Cooper TA (2012) RNA-binding proteins in microsatellite expansion disorders: mediators of RNA toxicity. Brain Res 1462:100–111. doi:10.1016/j.brainres.2012.02.030

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Du J, Aleff RA, Soragni E, Kalari K, Nie J, Tang X, Davila J, Kocher JP, Patel SV, Gottesfeld JM, Baratz KH, Wieben ED (2015) RNA toxicity and missplicing in the common eye disease fuchs endothelial corneal dystrophy. J Biol Chem 290:5979–5990. doi:10.1074/jbc.M114.621607

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Gendron TF, Belzil VV, Zhang YJ, Petrucelli L (2014) Mechanisms of toxicity in C9FTLD/ALS. Acta Neuropathol 127(3):359–376. doi:10.1007/s00401-013-1237-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Xu Z, Poidevin M, Li X, Li Y, Shu L, Nelson DL, Li H, Hales CM, Gearing M, Wingo TS, Jin P (2013) Expanded GGGGCC repeat RNA associated with amyotrophic lateral sclerosis and frontotemporal dementia causes neurodegeneration. Proc Natl Acad Sci USA 110(19):7778–7783

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Wojciechowska M, Olejniczak M, Galka-Marciniak P, Jazurek M, Krzyzosiak WJ (2014) RAN translation and frameshifting as translational challenges at simple repeats of human neurodegenerative disorders. Nucleic Acids Res 42:11849–11864. doi:10.1093/nar/gku794

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Butler JS, Napierala M (2015) Friedreich’s ataxia—a case of aberrant transcription termination? Transcription 6(2):33–36

    Article  PubMed  PubMed Central  Google Scholar 

  16. Takahashi K, Yamanaka S (2006) Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126:663–676. doi:10.1016/j.cell.2006.07.024

    Article  CAS  PubMed  Google Scholar 

  17. Takahashi K, Yamanaka S (2016) A decade of transcription factor-mediated reprogramming to pluripotency. Nat Rev Mol Cell Biol 17(3):183–193. doi:10.1038/nrm.2016.8

    Article  CAS  PubMed  Google Scholar 

  18. Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K, Yamanaka S (2007) Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131:861–872. doi:10.1016/j.cell.2007.11.019

    Article  CAS  PubMed  Google Scholar 

  19. Rasmussen MA, Holst B, Tumer Z, Johnsen MG, Zhou S, Stummann TC, Hyttel P, Clausen C (2014) Transient p53 suppression increases reprogramming of human fibroblasts without affecting apoptosis and DNA damage. Stem Cell Rep 3(3):404–413. doi:10.1016/j.stemcr.2014.07.006

    Article  CAS  Google Scholar 

  20. Malik N, Rao MS (2013) A review of the methods for human iPSC derivation. Methods Mol Biol 997:23–33. doi:10.1007/978-1-62703-348-0_3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Kang X, Yu Q, Huang Y, Song B, Chen Y, Gao X, He W, Sun X, Fan Y (2015) Effects of integrating and non-integrating reprogramming methods on copy number variation and genomic stability of human induced pluripotent stem cells. PLoS One 10(7):e0131128

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Consortium THi (2012) Induced pluripotent stem cells from patients with Huntington’s disease show CAG-repeat-expansion-associated phenotypes. Cell Stem Cell 11(2):264–278

    Article  CAS  Google Scholar 

  23. Jeon I, Lee N, Li JY, Park IH, Park KS, Moon J, Shim SH, Choi C, Chang DJ, Kwon J, Oh SH, Shin DA, Kim HS, Do JT, Lee DR, Kim M, Kang KS, Daley GQ, Brundin P, Song J (2012) Neuronal properties, in vivo effects, and pathology of a Huntington’s disease patient-derived induced pluripotent stem cells. Stem Cells 30(9):2054–2062. doi:10.1002/stem.1135

    Article  CAS  PubMed  Google Scholar 

  24. Cheng PH, Li CL, Chang YF, Tsai SJ, Lai YY, Chan AW, Chen CM, Yang SH (2013) miR-196a ameliorates phenotypes of Huntington disease in cell, transgenic mouse, and induced pluripotent stem cell models. Am J Hum Genet 93(2):306–312. doi:10.1016/j.ajhg.2013.05.025

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Chae JI, Kim DW, Lee N, Jeon YJ, Jeon I, Kwon J, Kim J, Soh Y, Lee DS, Seo KS, Choi NJ, Park BC, Kang SH, Ryu J, Oh SH, Shin DA, Lee DR, Do JT, Park IH, Daley GQ, Song J (2012) Quantitative proteomic analysis of induced pluripotent stem cells derived from a human Huntington’s disease patient. Biochem J 446:359–371. doi:10.1042/BJ20111495

    Article  CAS  PubMed  Google Scholar 

  26. Zhang N, An MC, Montoro D, Ellerby LM (2010) Characterization of human Huntington’s disease cell model from induced pluripotent stem cells. PLoS Curr 2:RRN1193. doi:10.1371/currents.RRN1193

    Article  PubMed  PubMed Central  Google Scholar 

  27. Szlachcic WJ, Switonski PM, Krzyzosiak WJ, Figlerowicz M, Figiel M (2015) Huntington disease iPSCs show early molecular changes in intracellular signaling, the expression of oxidative stress proteins and the p53 pathway. Dis Model Mech 8(9):1047–1057. doi:10.1242/dmm.019406

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Camnasio S, Delli Carri A, Lombardo A, Grad I, Mariotti C, Castucci A, Rozell B, Lo Riso P, Castiglioni V, Zuccato C, Rochon C, Takashima Y, Diaferia G, Biunno I, Gellera C, Jaconi M, Smith A, Hovatta O, Naldini L, Di Donato S, Feki A, Cattaneo E (2012) The first reported generation of several induced pluripotent stem cell lines from homozygous and heterozygous Huntington’s disease patients demonstrates mutation related enhanced lysosomal activity. Neurobiol Dis 46:41–51. doi:10.1016/j.nbd.2011.12.042

    Article  CAS  PubMed  Google Scholar 

  29. Cha MY, Kim DK, Mook-Jung I (2015) The role of mitochondrial DNA mutation on neurodegenerative diseases. Exp Mol Med 47:e150

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Guo X, Disatnik MH, Monbureau M, Shamloo M, Mochly-Rosen D, Qi X (2013) Inhibition of mitochondrial fragmentation diminishes Huntington’s disease-associated neurodegeneration. J Clin Investig 123(12):5371–5388. doi:10.1172/JCI70911

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Xia G, Ashizawa T (2015) Dynamic changes of nuclear RNA foci in proliferating DM1 cells. Histochem Cell Biol. doi:10.1007/s00418-015-1315-5

    PubMed  PubMed Central  Google Scholar 

  32. Xia G, Santostefano KE, Goodwin M, Liu J, Subramony SH, Swanson MS, Terada N, Ashizawa T (2013) Generation of neural cells from DM1 induced pluripotent stem cells as cellular model for the study of central nervous system neuropathogenesis. Cell Reprogram 15(2):166–177. doi:10.1089/cell.2012.0086

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Almeida S, Gascon E, Tran H, Chou HJ, Gendron TF, Degroot S, Tapper AR, Sellier C, Charlet-Berguerand N, Karydas A, Seeley WW, Boxer AL, Petrucelli L, Miller BL, Gao FB (2013) Modeling key pathological features of frontotemporal dementia with C9ORF72 repeat expansion in iPSC-derived human neurons. Acta Neuropathol 126(3):385–399. doi:10.1007/s00401-013-1149-y

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Hansen RS, Gartler SM, Scott CR, Chen SH, Laird CD (1992) Methylation analysis of CGG sites in the CpG island of the human FMR1 gene. Hum Mol Genet 1(8):571–578

    Article  CAS  PubMed  Google Scholar 

  35. Urbach A, Bar-Nur O, Daley GQ, Benvenisty N (2010) Differential modeling of fragile X syndrome by human embryonic stem cells and induced pluripotent stem cells. Cell Stem Cell 6:407–411. doi:10.1016/j.stem.2010.04.005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. de Esch CE, Ghazvini M, Loos F, Schelling-Kazaryan N, Widagdo W, Munshi ST, van der Wal E, Douben H, Gunhanlar N, Kushner SA, Pijnappel WW, de Vrij FM, Geijsen N, Gribnau J, Willemsen R (2014) Epigenetic characterization of the FMR1 promoter in induced pluripotent stem cells from human fibroblasts carrying an unmethylated full mutation. Stem cell reports 3(4):548–555. doi:10.1016/j.stemcr.2014.07.013

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  37. Sheridan SD, Theriault KM, Reis SA, Zhou F, Madison JM, Daheron L, Loring JF, Haggarty SJ (2011) Epigenetic characterization of the FMR1 gene and aberrant neurodevelopment in human induced pluripotent stem cell models of fragile X syndrome. PLoS One 6:e26203. doi:10.1371/journal.pone.0026203

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Bar-Nur O, Caspi I, Benvenisty N (2012) Molecular analysis of FMR1 reactivation in fragile-X induced pluripotent stem cells and their neuronal derivatives. J Mol Cell Biol 4:180–183. doi:10.1093/jmcb/mjs007

    Article  PubMed  CAS  Google Scholar 

  39. Doers ME, Musser MT, Nichol R, Berndt ER, Baker M, Gomez TM, Zhang SC, Abbeduto L, Bhattacharyya A (2014) iPSC-derived forebrain neurons from FXS individuals show defects in initial neurite outgrowth. Stem Cells Dev 23(15):1777–1787. doi:10.1089/scd.2014.0030

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Smeets HJ, Smits AP, Verheij CE, Theelen JP, Willemsen R, van de Burgt I, Hoogeveen AT, Oosterwijk JC, Oostra BA (1995) Normal phenotype in two brothers with a full FMR1 mutation. Hum Mol Genet 4(11):2103–2108

    Article  CAS  PubMed  Google Scholar 

  41. Liu J, Koscielska KA, Cao Z, Hulsizer S, Grace N, Mitchell G, Nacey C, Githinji J, McGee J, Garcia-Arocena D, Hagerman RJ, Nolta J, Pessah IN, Hagerman PJ (2012) Signaling defects in iPSC-derived fragile X premutation neurons. Hum Mol Genet 21:3795–3805. doi:10.1093/hmg/dds207

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Eigentler A, Boesch S, Schneider R, Dechant G, Nat R (2013) Induced pluripotent stem cells from friedreich ataxia patients fail to upregulate frataxin during in vitro differentiation to peripheral sensory neurons. Stem Cells Dev 22(24):3271–3282. doi:10.1089/scd.2013.0126

    Article  CAS  PubMed  Google Scholar 

  43. Lee YK, Ho PW, Schick R, Lau YM, Lai WH, Zhou T, Li Y, Ng KM, Ho SL, Esteban MA, Binah O, Tse HF, Siu CW (2013) Modeling of Friedreich ataxia-related iron overloading cardiomyopathy using patient-specific-induced pluripotent stem cells. Pflugers Arch 466(9):1831–1844. doi:10.1007/s00424-013-1414-x

    Article  PubMed  CAS  Google Scholar 

  44. Hick A, Wattenhofer-Donze M, Chintawar S, Tropel P, Simard JP, Vaucamps N, Gall D, Lambot L, Andre C, Reutenauer L, Rai M, Teletin M, Messaddeq N, Schiffmann SN, Viville S, Pearson CE, Pandolfo M, Puccio H (2013) Neurons and cardiomyocytes derived from induced pluripotent stem cells as a model for mitochondrial defects in Friedreich’s ataxia. Dis Model Mech 6:608–621. doi:10.1242/dmm.010900

    Article  CAS  PubMed  Google Scholar 

  45. Liu J, Verma PJ, Evans-Galea MV, Delatycki MB, Michalska A, Leung J, Crombie D, Sarsero JP, Williamson R, Dottori M, Pebay A (2011) Generation of induced pluripotent stem cell lines from Friedreich ataxia patients. Stem cell reviews 7(3):703–713. doi:10.1007/s12015-010-9210-x

    Article  CAS  PubMed  Google Scholar 

  46. Ku S, Soragni E, Campau E, Thomas EA, Altun G, Laurent LC, Loring JF, Napierala M, Gottesfeld JM (2010) Friedreich’s ataxia induced pluripotent stem cells model intergenerational GAATTC triplet repeat instability. Cell Stem Cell 7:631–637. doi:10.1016/j.stem.2010.09.014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Wells RD, Dere R, Hebert ML, Napierala M, Son LS (2005) Advances in mechanisms of genetic instability related to hereditary neurological diseases. Nucleic Acids Res 33:3785–3798. doi:10.1093/nar/gki697

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Figura G, Koscianska E, Krzyzosiak WJ (2015) In vitro expansion of CAG, CAA, and mixed CAG/CAA repeats. Int J Mol Sci 16(8):18741–18751

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Lopez Castel A, Cleary JD, Pearson CE (2010) Repeat instability as the basis for human diseases and as a potential target for therapy. Nat Rev Mol Cell Biol 11:165–170. doi:10.1038/nrm2854

    Article  PubMed  CAS  Google Scholar 

  50. Pearson CE, Nichol Edamura K, Cleary JD (2005) Repeat instability: mechanisms of dynamic mutations. Nat Rev Genet 6:729–742. doi:10.1038/nrg1689

    Article  CAS  PubMed  Google Scholar 

  51. Park IH, Arora N, Huo H, Maherali N, Ahfeldt T, Shimamura A, Lensch MW, Cowan C, Hochedlinger K, Daley GQ (2008) Disease-specific induced pluripotent stem cells. Cell 134:877–886. doi:10.1016/j.cell.2008.07.041

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. An MC, Zhang N, Scott G, Montoro D, Wittkop T, Mooney S, Melov S, Ellerby LM (2012) Genetic correction of Huntington’s disease phenotypes in induced pluripotent stem cells. Cell Stem Cell 11:253–263. doi:10.1016/j.stem.2012.04.026

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Xia G, Santostefano K, Hamazaki T, Liu J, Subramony SH, Terada N, Ashizawa T (2013) Generation of human-induced pluripotent stem cells to model spinocerebellar ataxia type 2 in vitro. J Mol Neurosci MN 51(2):237–248. doi:10.1007/s12031-012-9930-2

    Article  CAS  PubMed  Google Scholar 

  54. Koch P, Breuer P, Peitz M, Jungverdorben J, Kesavan J, Poppe D, Doerr J, Ladewig J, Mertens J, Tuting T, Hoffmann P, Klockgether T, Evert BO, Wullner U, Brustle O (2011) Excitation-induced ataxin-3 aggregation in neurons from patients with Machado-Joseph disease. Nature 480:543–546. doi:10.1038/nature10671

    CAS  PubMed  Google Scholar 

  55. Nihei Y, Ito D, Okada Y, Akamatsu W, Yagi T, Yoshizaki T, Okano H, Suzuki N (2013) Enhanced aggregation of androgen receptor in induced pluripotent stem cell-derived neurons from spinal and bulbar muscular atrophy. J Biol Chem 288:8043–8052. doi:10.1074/jbc.M112.408211

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Grunseich C, Zukosky K, Kats IR, Ghosh L, Harmison GG, Bott LC, Rinaldi C, Chen KL, Chen G, Boehm M, Fischbeck KH (2014) Stem cell-derived motor neurons from spinal and bulbar muscular atrophy patients. Neurobiol Dis 70:12–20. doi:10.1016/j.nbd.2014.05.038

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Luo Y, Fan Y, Zhou B, Xu Z, Chen Y, Sun X (2012) Generation of induced pluripotent stem cells from skin fibroblasts of a patient with olivopontocerebellar atrophy. Tohoku J Exp Med 226:151–159

    Article  CAS  PubMed  Google Scholar 

  58. Du J, Campau E, Soragni E, Jespersen C, Gottesfeld JM (2013) Length-dependent CTG.CAG triplet-repeat expansion in myotonic dystrophy patient-derived induced pluripotent stem cells. Hum Mol Genet 22:5276–5287. doi:10.1093/hmg/ddt386

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Jaworski A, Rosche WA, Gellibolian R, Kang S, Shimizu M, Bowater RP, Sinden RR, Wells RD (1995) Mismatch repair in Escherichia coli enhances instability of (CTG)n triplet repeats from human hereditary diseases. Proc Natl Acad Sci USA 92(24):11019–11023

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Du J, Campau E, Soragni E, Ku S, Puckett JW, Dervan PB, Gottesfeld JM (2012) Role of mismatch repair enzymes in GAA.TTC triplet-repeat expansion in Friedreich ataxia induced pluripotent stem cells. J Biol Chem 287:29861–29872. doi:10.1074/jbc.M112.391961

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Donnelly CJ, Zhang PW, Pham JT, Haeusler AR, Mistry NA, Vidensky S, Daley EL, Poth EM, Hoover B, Fines DM, Maragakis N, Tienari PJ, Petrucelli L, Traynor BJ, Wang J, Rigo F, Bennett CF, Blackshaw S, Sattler R, Rothstein JD (2013) RNA toxicity from the ALS/FTD C9ORF72 expansion is mitigated by antisense intervention. Neuron 80(2):415–428. doi:10.1016/j.neuron.2013.10.015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Sareen D, O’Rourke JG, Meera P, Muhammad AK, Grant S, Simpkinson M, Bell S, Carmona S, Ornelas L, Sahabian A, Gendron T, Petrucelli L, Baughn M, Ravits J, Harms MB, Rigo F, Bennett CF, Otis TS, Svendsen CN, Baloh RH (2013) Targeting RNA foci in iPSC-derived motor neurons from ALS patients with a C9ORF72 repeat expansion. Sci Transl Med 5(208):208ra149

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  63. Hu BY, Weick JP, Yu J, Ma LX, Zhang XQ, Thomson JA, Zhang SC (2010) Neural differentiation of human induced pluripotent stem cells follows developmental principles but with variable potency. Proc Natl Acad Sci 107:4335–4340. doi:10.1073/pnas.0910012107

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Murry CE, Keller G (2008) Differentiation of embryonic stem cells to clinically relevant populations: lessons from embryonic development. Cell 132(4):661–680

    Article  CAS  PubMed  Google Scholar 

  65. Sandoe J, Eggan K (2013) Opportunities and challenges of pluripotent stem cell neurodegenerative disease models. Nat Neurosci 16(7):780–789

    Article  CAS  PubMed  Google Scholar 

  66. Takazawa T, Croft GF, Amoroso MW, Studer L, Wichterle H, Macdermott AB (2012) Maturation of spinal motor neurons derived from human embryonic stem cells. PLoS One 7:e40154. doi:10.1371/journal.pone.0040154

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Hernandez F, Perez M, de Barreda EG, Goni-Oliver P, Avila J (2008) Tau as a molecular marker of development, aging and neurodegenerative disorders. Curr Aging Sci 1(1):56–61

    Article  CAS  PubMed  Google Scholar 

  68. Compagnucci C, Nizzardo M, Corti S, Zanni G, Bertini E (2013) In vitro neurogenesis: development and functional implications of iPSC technology. Cell Mol Life Sci CMLS 71(9):1623–1639. doi:10.1007/s00018-013-1511-1

    Article  PubMed  CAS  Google Scholar 

  69. Velasco I, Salazar P, Giorgetti A, Ramos-Mejia V, Castano J, Romero-Moya D, Menendez P (2014) Concise review: generation of neurons from somatic cells of healthy individuals and neurological patients through induced pluripotency or direct conversion. Stem Cells 32(11):2811–2817. doi:10.1002/stem.1782

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Pre D, Nestor MW, Sproul AA, Jacob S, Koppensteiner P, Chinchalongporn V, Zimmer M, Yamamoto A, Noggle SA, Arancio O (2014) A time course analysis of the electrophysiological properties of neurons differentiated from human induced pluripotent stem cells (iPSCs). PLoS One 9:e103418. doi:10.1371/journal.pone.0103418

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  71. Koehler KR, Tropel P, Theile JW, Kondo T, Cummins TR, Viville S, Hashino E (2011) Extended passaging increases the efficiency of neural differentiation from induced pluripotent stem cells. BMC Neurosci 12(1):82. doi:10.1186/1471-2202-12-82

    Article  PubMed  PubMed Central  Google Scholar 

  72. Devlin AC, Burr K, Borooah S, Foster JD, Cleary EM, Geti I, Vallier L, Shaw CE, Chandran S, Miles GB (2014) Human iPSC-derived motoneurons harbouring TARDBP or C9ORF72 ALS mutations are dysfunctional despite maintaining viability. Nat Commun 6:5999

    Article  CAS  Google Scholar 

  73. Ebert AD, Shelley BC, Hurley AM, Onorati M, Castiglioni V, Patitucci TN, Svendsen SP, Mattis VB, McGivern JV, Schwab AJ, Sareen D, Kim HW, Cattaneo E, Svendsen CN (2013) EZ spheres: a stable and expandable culture system for the generation of pre-rosette multipotent stem cells from human ESCs and iPSCs. Stem Cell Res 10(3):417–427. doi:10.1016/j.scr.2013.01.009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Kurosawa H (2007) Methods for inducing embryoid body formation: in vitro differentiation system of embryonic stem cells. J Biosci Bioeng 103(5):389–398

    Article  CAS  PubMed  Google Scholar 

  75. Elkabetz Y, Panagiotakos G, Al Shamy G, Socci ND, Tabar V, Studer L (2008) Human ES cell-derived neural rosettes reveal a functionally distinct early neural stem cell stage. Genes Dev 22(2):152–165

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Kawasaki H, Mizuseki K, Nishikawa S, Kaneko S, Kuwana Y, Nakanishi S, Nishikawa SI, Sasai Y (2000) Induction of midbrain dopaminergic neurons from ES cells by stromal cell-derived inducing activity. Neuron 28(1):31–40

    Article  CAS  PubMed  Google Scholar 

  77. Yang N, Ng YH, Pang ZP, Sudhof TC, Wernig M (2011) Induced neuronal cells: how to make and define a neuron. Cell Stem Cell 9(6):517–525

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Li XJ, Zhang X, Johnson MA, Wang ZB, Lavaute T, Zhang SC (2009) Coordination of sonic hedgehog and Wnt signaling determines ventral and dorsal telencephalic neuron types from human embryonic stem cells. Development 136(23):4055–4063. doi:10.1242/dev.036624

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Ma X, Turnbull P, Peterson R, Turnbull J (2013) Trophic and proliferative effects of Shh on motor neurons in embryonic spinal cord culture from wildtype and G93A SOD1 mice. BMC Neurosci 14:119

    Article  PubMed  PubMed Central  Google Scholar 

  80. Ambasudhan R, Talantova M, Coleman R, Yuan X, Zhu S, Lipton SA, Ding S (2011) Direct reprogramming of adult human fibroblasts to functional neurons under defined conditions. Cell Stem Cell 9(2):113–118. doi:10.1016/j.stem.2011.07.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Purro SA, Dickins EM, Salinas PC (2012) The secreted Wnt antagonist Dickkopf-1 is required for amyloid beta-mediated synaptic loss. J Neurosci 32(10):3492–3498

    Article  CAS  PubMed  Google Scholar 

  82. Laeng P, Pitts RL, Lemire AL, Drabik CE, Weiner A, Tang H, Thyagarajan R, Mallon BS, Altar CA (2004) The mood stabilizer valproic acid stimulates GABA neurogenesis from rat forebrain stem cells. J Neurochem 91(1):238–251. doi:10.1111/j.1471-4159.2004.02725.x

    Article  CAS  PubMed  Google Scholar 

  83. Chatzi C, Brade T, Duester G (2011) Retinoic acid functions as a key GABAergic differentiation signal in the basal ganglia. PLoS Biol 9(4):e1000609. doi:10.1371/journal.pbio.1000609

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Lee S, Lee B, Lee JW, Lee SK (2009) Retinoid signaling and neurogenin2 function are coupled for the specification of spinal motor neurons through a chromatin modifier CBP. Neuron 62(5):641–654. doi:10.1016/j.neuron.2009.04.025

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Urbanek MO, Krzyzosiak WJ (2016) RNA FISH for detecting expanded repeats in human diseases. Methods 98:115–123. doi:10.1016/j.ymeth.2015.11.017

    Article  CAS  PubMed  Google Scholar 

  86. Wojciechowska M, Krzyzosiak WJ (2011) Cellular toxicity of expanded RNA repeats: focus on RNA foci. Hum Mol Genet 20:3811–3821. doi:10.1093/hmg/ddr299

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Pettersson OJ, Aagaard L, Jensen TG, Damgaard CK (2015) Molecular mechanisms in DM1—a focus on foci. Nucleic Acids Res. doi:10.1093/nar/gkv029

    Google Scholar 

  88. Ring KL, An MC, Zhang N, O’Brien RN, Ramos EM, Gao F, Atwood R, Bailus BJ, Melov S, Mooney SD, Coppola G, Ellerby LM (2015) Genomic analysis reveals disruption of striatal neuronal development and therapeutic targets in human Huntington’s disease neural stem cells. Stem Cell Rep 5(6):1023–1038

    Article  CAS  Google Scholar 

  89. Mattis VB, Tom C, Akimov S, Saeedian J, Ostergaard ME, Southwell AL, Doty CN, Ornelas L, Sahabian A, Lenaeus L, Mandefro B, Sareen D, Arjomand J, Hayden MR, Ross CA, Svendsen CN (2015) HD iPSC-derived neural progenitors accumulate in culture and are susceptible to BDNF withdrawal due to glutamate toxicity. Hum Mol Genet 24(11):3257–3271

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Liu Y, Xue Y, Ridley S, Zhang D, Rezvani K, Fu XD, Wang H (2014) Direct reprogramming of Huntington’s disease patient fibroblasts into neuron-like cells leads to abnormal neurite outgrowth, increased cell death, and aggregate formation. PLoS One 9:e109621. doi:10.1371/journal.pone.0109621

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  91. Vonsattel JP, DiFiglia M (1998) Huntington disease. J Neuropathol Exp Neurol 57(5):369–384

    Article  CAS  PubMed  Google Scholar 

  92. Lu XH, Mattis VB, Wang N, Al-Ramahi I, van den Berg N, Fratantoni SA, Waldvogel H, Greiner E, Osmand A, Elzein K, Xiao J, Dijkstra S, de Pril R, Vinters HV, Faull R, Signer E, Kwak S, Marugan JJ, Botas J, Fischer DF, Svendsen CN, Munoz-Sanjuan I, Yang XW (2014) Targeting ATM ameliorates mutant Huntingtin toxicity in cell and animal models of Huntington’s disease. Sci Transl Med 6(268):268ra178. doi:10.1126/scitranslmed.3010523

    Article  PubMed  CAS  Google Scholar 

  93. Yao Y, Cui X, Al-Ramahi I, Sun X, Li B, Hou J, Difiglia M, Palacino J, Wu ZY, Ma L, Botas J, Lu B (2015) A striatal-enriched intronic GPCR modulates huntingtin levels and toxicity. eLife 4:e05449. doi:10.7554/eLife.05449

    Article  PubMed Central  Google Scholar 

  94. Chiu FL, Lin JT, Chuang CY, Chien T, Chen CM, Chen KH, Hsiao HY, Lin YS, Chern Y, Kuo HC (2015) Elucidating the role of the A2A adenosine receptor in neurodegeneration using neurons derived from Huntington’s disease iPSCs. Hum Mol Genet 24(21):6066–6079

    Article  CAS  PubMed  Google Scholar 

  95. Jeon I, Choi C, Lee N, Im W, Kim M, Oh SH, Park IH, Kim HS, Song J (2014) In vivo roles of a patient-derived induced pluripotent stem cell line (HD72-iPSC) in the YAC128 model of Huntington’s disease. Int J Stem Cells 7:43–47. doi:10.15283/ijsc.2014.7.1.43

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Fratta P, Mizielinska S, Nicoll AJ, Zloh M, Fisher EM, Parkinson G, Isaacs AM (2012) C9orf72 hexanucleotide repeat associated with amyotrophic lateral sclerosis and frontotemporal dementia forms RNA G-quadruplexes. Sci Rep 2:1016

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  97. Reddy K, Zamiri B, Stanley SY, Macgregor RB Jr, Pearson CE (2013) The disease-associated r(GGGGCC)n repeat from the C9orf72 gene forms tract length-dependent uni- and multimolecular RNA G-quadruplex structures. J Biol Chem 288(14):9860–9866

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Hideyama T, Yamashita T, Suzuki T, Tsuji S, Higuchi M, Seeburg PH, Takahashi R, Misawa H, Kwak S (2010) Induced loss of ADAR2 engenders slow death of motor neurons from Q/R site-unedited GluR2. J Neurosci 30(36):11917–11925

    Article  CAS  PubMed  Google Scholar 

  99. Zhang K, Donnelly CJ, Haeusler AR, Grima JC, Machamer JB, Steinwald P, Daley EL, Miller SJ, Cunningham KM, Vidensky S, Gupta S, Thomas MA, Hong I, Chiu SL, Huganir RL, Ostrow LW, Matunis MJ, Wang J, Sattler R, Lloyd TE, Rothstein JD (2015) The C9orf72 repeat expansion disrupts nucleocytoplasmic transport. Nature 525(7567):56–61

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Schweizer Burguete A, Almeida S, Gao FB, Kalb R, Akins MR, Bonini NM (2015) GGGGCC microsatellite RNA is neuritically localized, induces branching defects, and perturbs transport granule function. eLife 4:e08881. doi:10.7554/eLife.08881

    Article  Google Scholar 

  101. Satoh J, Yamamoto Y, Kitano S, Takitani M, Asahina N, Kino Y (2014) Molecular network analysis suggests a logical hypothesis for the pathological role of c9orf72 in amyotrophic lateral sclerosis/frontotemporal dementia. J Cent Nerv Syst Dis 6:69–78. doi:10.4137/JCNSD.S18103

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Kumari D, Swaroop M, Southall N, Huang W, Zheng W, Usdin K (2015) High-throughput screening to identify compounds that increase fragile X mental retardation protein expression in neural stem cells differentiated from fragile X syndrome patient-derived induced pluripotent stem cells. Stem Cells Transl Med 4(7):800–808

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Rusmini P, Simonini F, Crippa V, Bolzoni E, Onesto E, Cagnin M, Sau D, Ferri N, Poletti A (2011) 17-AAG increases autophagic removal of mutant androgen receptor in spinal and bulbar muscular atrophy. Neurobiol Dis 41:83–95. doi:10.1016/j.nbd.2010.08.023

    Article  CAS  PubMed  Google Scholar 

  104. Soragni E, Miao W, Iudicello M, Jacoby D, De Mercanti S, Clerico M, Longo F, Piga A, Ku S, Campau E, Du J, Penalver P, Rai M, Madara JC, Nazor K, O’Connor M, Maximov A, Loring JF, Pandolfo M, Durelli L, Gottesfeld JM, Rusche JR (2014) Epigenetic therapy for Friedreich ataxia. Ann Neurol 76(4):489–508. doi:10.1002/ana.24260

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Shan B, Xu C, Zhang Y, Xu T, Gottesfeld JM, Yates JR 3rd (2014) Quantitative proteomic analysis identifies targets and pathways of a 2-aminobenzamide HDAC inhibitor in friedreich’s ataxia patient iPSC-derived neural stem cells. J Proteome Res 13(11):4558–4566. doi:10.1021/pr500514r

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Singh AM, Adjan Steffey VV, Yeshi T, Allison DW (2015) Gene editing in human pluripotent stem cells: choosing the correct path. m-Cells—choosing-the-correct-path/630 [pii]. J Stem Cell Regen Biol 1:(1)

  107. An MC, O’Brien RN, Zhang N, Patra BN, De La Cruz M, Ray A, Ellerby LM (2014) Polyglutamine disease modeling: epitope based screen for homologous recombination using CRISPR/Cas9 system. PLoS Curr. doi:10.1371/currents.hd.0242d2e7ad72225efa72f6964589369a

    PubMed  PubMed Central  Google Scholar 

  108. Park CY, Halevy T, Lee DR, Sung JJ, Lee JS, Yanuka O, Benvenisty N, Kim DW (2015) Reversion of FMR1 methylation and silencing by editing the triplet repeats in fragile X iPSC-derived neurons. Cell Rep 13(2):234–241

    Article  CAS  PubMed  Google Scholar 

  109. Li Y, Polak U, Bhalla A, Rozwadowska N, Butler JS, Lynch D, Dent SY, Napierala M (2015) Excision of expanded GAA repeats alleviates the molecular phenotype of Friedreich’s ataxia. Mol Ther 23(6):1055–1065. doi:10.1038/mt.2015.41

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Xia G, Gao Y, Jin S, Subramony S, Terada N, Ranum LP, Swanson MS, Ashizawa T (2014) Genome modification leads to phenotype reversal in human myotonic dystrophy type 1 iPS-cell derived neural stem cells. Stem Cells 33(6):1829–1838. doi:10.1002/stem.1970

    Article  CAS  Google Scholar 

  111. Juopperi TA, Kim WR, Chiang CH, Yu H, Margolis RL, Ross CA, Ming GL, Song H (2012) Astrocytes generated from patient induced pluripotent stem cells recapitulate features of Huntington's disease patient cells. Mol Brain 5:17. doi:10.1186/1756-6606-5-17

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Kaufmann M, Schuffenhauer A, Fruh I, Klein J, Thiemeyer A, Rigo P, Gomez-Mancilla B, Heidinger-Millot V, Bouwmeester T, Schopfer U, Mueller M, Fodor BD, Cobos-Correa A (2015) High-Throughput Screening Using iPSC-Derived Neuronal Progenitors to Identify Compounds Counteracting Epigenetic Gene Silencing in Fragile X Syndrome. J biomol screen 20(9):1101–1111. doi:10.1177/1087057115588287

    Article  CAS  Google Scholar 

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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.

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    1. Department of Molecular Biomedicine, Institute of Bioorganic Chemistry, Polish Academy of Sciences, Noskowskiego 12/14 Str., 61-704, Poznan, Poland

      Edyta Jaworska, Emilia Kozlowska, Pawel M. Switonski & Wlodzimierz J. Krzyzosiak

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    2. Emilia Kozlowska
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    E. Jaworska, E. Kozlowska and P. M. Switonski contributed equally to this work.

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    Jaworska, E., Kozlowska, E., Switonski, P.M. et al. Modeling simple repeat expansion diseases with iPSC technology. Cell. Mol. Life Sci. 73, 4085–4100 (2016). https://doi.org/10.1007/s00018-016-2284-0

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