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Progerin-Induced Transcriptional Changes in Huntington’s Disease Human Pluripotent Stem Cell-Derived Neurons

Abstract

Huntington’s disease (HD) is a neurodegenerative late-onset genetic disorder caused by CAG expansions in the coding region of the Huntingtin (HTT) gene, resulting in a poly-glutamine (polyQ) expanded HTT protein. Considerable efforts have been devoted for studying HD and other polyQ diseases using animal models and cell culture systems, but no treatment currently exists. Human embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) offer an elegant solution for modeling human diseases. However, as embryonic or rejuvenated cells, respectively, these pluripotent stem cells (PSCs) do not recapitulate the late-onset feature of the disease. Here, we applied a robust and rapid differentiation protocol to derive electrophysiologically active striatal GABAergic neurons from human wild-type (WT) and HD ESCs and iPSCs. RNA-seq analyses revealed that HD and WT PSC-derived neurons are highly similar in their gene expression patterns. Interestingly, ectopic expression of Progerin in both WT and HD neurons exacerbated the otherwise non-significant changes in gene expression between these cells, revealing IGF1 and genes involved in neurogenesis and nervous system development as consistently altered in the HD cells. This work provides a useful tool for modeling HD in human PSCs and reveals potential molecular targets altered in HD neurons.

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Data Availability

All data are available at through GEO (GSE111622).

References

  1. 1.

    Milnerwood AJ, Raymond LA (2010) Early synaptic pathophysiology in neurodegeneration: insights from Huntington’s disease. Trends Neurosci 33(11):513–523. https://doi.org/10.1016/j.tins.2010.08.002

  2. 2.

    Andrew SE, Goldberg YP, Kremer B, Telenius H, Theilmann J, Adam S, Starr E, Squitieri F et al (1993) The relationship between trinucleotide (CAG) repeat length and clinical features of Huntington’s disease. Nat Genet 4(4):398–403. https://doi.org/10.1038/ng0893-398

  3. 3.

    Myers RH, MacDonald ME, Koroshetz WJ, Duyao MP, Ambrose CM, Taylor SA, Barnes G, Srinidhi J et al (1993) De novo expansion of a (CAG)n repeat in sporadic Huntington’s disease. Nat Genet 5(2):168–173. https://doi.org/10.1038/ng1093-168

  4. 4.

    Pouladi MA, Morton AJ, Hayden MR (2013) Choosing an animal model for the study of Huntington’s disease. Nat Rev Neurosci 14(10):708–721. https://doi.org/10.1038/nrn3570

  5. 5.

    Chen Y, Carter RL, Cho IK, Chan AW (2014) Cell-based therapies for Huntington’s disease. Drug Discov Today 19(7):980–984. https://doi.org/10.1016/j.drudis.2014.02.012

  6. 6.

    Jung YW, Hysolli E, Kim KY, Tanaka Y, Park IH (2012) Human induced pluripotent stem cells and neurodegenerative disease: prospects for novel therapies. Curr Opin Neurol 25(2):125–130. https://doi.org/10.1097/WCO.0b013e3283518226

  7. 7.

    Halevy T, Urbach A (2014) Comparing ESC and iPSC-based models for human genetic disorders. J Clin Med 3(4):1146–1162. https://doi.org/10.3390/jcm3041146

  8. 8.

    Connor B (2018) Concise review: the use of stem cells for understanding and treating Huntington’s disease. Stem Cells 36(2):146–160. https://doi.org/10.1002/stem.2747

  9. 9.

    Aubry L, Bugi A, Lefort N, Rousseau F, Peschanski M, Perrier AL (2008) Striatal progenitors derived from human ES cells mature into DARPP32 neurons in vitro and in quinolinic acid-lesioned rats. Proc Natl Acad Sci U S A 105(43):16707–16712. https://doi.org/10.1073/pnas.0808488105

  10. 10.

    Ma L, Hu B, Liu Y, Vermilyea SC, Liu H, Gao L, Sun Y, Zhang X et al (2012) Human embryonic stem cell-derived GABA neurons correct locomotion deficits in quinolinic acid-lesioned mice. Cell Stem Cell 10(4):455–464. https://doi.org/10.1016/j.stem.2012.01.021

  11. 11.

    Consortium HDi (2012) Induced pluripotent stem cells from patients with Huntington’s disease show CAG-repeat-expansion-associated phenotypes. Cell Stem Cell 11(2):264–278. https://doi.org/10.1016/j.stem.2012.04.027

  12. 12.

    Delli Carri A, Onorati M, Lelos MJ, Castiglioni V, Faedo A, Menon R, Camnasio S, Vuono R et al (2013) Developmentally coordinated extrinsic signals drive human pluripotent stem cell differentiation toward authentic DARPP-32+ medium-sized spiny neurons. Development 140(2):301–312. https://doi.org/10.1242/dev.084608

  13. 13.

    Miller JD, Ganat YM, Kishinevsky S, Bowman RL, Liu B, Tu EY, Mandal PK, Vera E et al (2013) Human iPSC-based modeling of late-onset disease via progerin-induced aging. Cell Stem Cell 13(6):691–705. https://doi.org/10.1016/j.stem.2013.11.006

  14. 14.

    Bradley CK, Scott HA, Chami O, Peura TT, Dumevska B, Schmidt U, Stojanov T (2011) Derivation of Huntington’s disease-affected human embryonic stem cell lines. Stem Cells Dev 20(3):495–502. https://doi.org/10.1089/scd.2010.0120

  15. 15.

    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(5):861–872. doi:S0092-8674(07)01471-7. https://doi.org/10.1016/j.cell.2007.11.019

  16. 16.

    Dobin A, Davis CA, Schlesinger F, Drenkow J, Zaleski C, Jha S, Batut P, Chaisson M et al (2013) STAR: ultrafast universal RNA-seq aligner. Bioinformatics 29(1):15–21. https://doi.org/10.1093/bioinformatics/bts635

  17. 17.

    Derr A, Yang C, Zilionis R, Sergushichev A, Blodgett DM, Redick S, Bortell R, Luban J et al (2016) End sequence analysis toolkit (ESAT) expands the extractable information from single-cell RNA-seq data. Genome Res 26(10):1397–1410. https://doi.org/10.1101/gr.207902.116

  18. 18.

    Mi H, Huang X, Muruganujan A, Tang H, Mills C, Kang D, Thomas PD (2017) PANTHER version 11: expanded annotation data from gene ontology and Reactome pathways, and data analysis tool enhancements. Nucleic Acids Res 45(D1):D183–D189. https://doi.org/10.1093/nar/gkw1138

  19. 19.

    Chambers SM, Fasano CA, Papapetrou EP, Tomishima M, Sadelain M, Studer L (2009) Highly efficient neural conversion of human ES and iPS cells by dual inhibition of SMAD signaling. Nat Biotechnol 27(3):275–280. https://doi.org/10.1038/nbt.1529

  20. 20.

    Nicoleau C, Varela C, Bonnefond C, Maury Y, Bugi A, Aubry L, Viegas P, Bourgois-Rocha F et al (2013) Embryonic stem cells neural differentiation qualifies the role of Wnt/beta-catenin signals in human telencephalic specification and regionalization. Stem Cells 31(9):1763–1774. https://doi.org/10.1002/stem.1462

  21. 21.

    Matsuda K, Kondoh H (2014) Dkk1-dependent inhibition of Wnt signaling activates Hesx1 expression through its 5′ enhancer and directs forebrain precursor development. Genes Cells 19(5):374–385. https://doi.org/10.1111/gtc.12136

  22. 22.

    Huang SM, Mishina YM, Liu S, Cheung A, Stegmeier F, Michaud GA, Charlat O, Wiellette E et al (2009) Tankyrase inhibition stabilizes axin and antagonizes Wnt signalling. Nature 461(7264):614–620. https://doi.org/10.1038/nature08356

  23. 23.

    Chen JK, Taipale J, Young KE, Maiti T, Beachy PA (2002) Small molecule modulation of smoothened activity. Proc Natl Acad Sci U S A 99(22):14071–14076. https://doi.org/10.1073/pnas.182542899

  24. 24.

    Gorojankina T, Hoch L, Faure H, Roudaut H, Traiffort E, Schoenfelder A, Girard N, Mann A et al (2013) Discovery, molecular and pharmacological characterization of GSA-10, a novel small-molecule positive modulator of smoothened. Mol Pharmacol 83(5):1020–1029. https://doi.org/10.1124/mol.112.084590

  25. 25.

    Ge H, Tan L, Wu P, Yin Y, Liu X, Meng H, Cui G, Wu N et al (2015) Poly-L-ornithine promotes preferred differentiation of neural stem/progenitor cells via ERK signalling pathway. Sci Rep 5:15535. https://doi.org/10.1038/srep15535

  26. 26.

    Prapong T, Uemura E, Hsu WH (2001) G protein and cAMP-dependent protein kinase mediate amyloid beta-peptide inhibition of neuronal glucose uptake. Exp Neurol 167(1):59–64. https://doi.org/10.1006/exnr.2000.7519

  27. 27.

    Chao MV (2003) Neurotrophins and their receptors: a convergence point for many signalling pathways. Nat Rev Neurosci 4(4):299–309. https://doi.org/10.1038/nrn1078

  28. 28.

    Chorev E, Yarom Y, Lampl I (2007) Rhythmic episodes of subthreshold membrane potential oscillations in the rat inferior olive nuclei in vivo. J Neurosci 27(19):5043–5052. https://doi.org/10.1523/JNEUROSCI.5187-06.2007

  29. 29.

    West EL, Gonzalez-Cordero A, Hippert C, Osakada F, Martinez-Barbera JP, Pearson RA, Sowden JC, Takahashi M et al (2012) Defining the integration capacity of embryonic stem cell-derived photoreceptor precursors. Stem Cells 30(7):1424–1435. https://doi.org/10.1002/stem.1123

  30. 30.

    Conforti P, Besusso D, Bocchi VD, Faedo A, Cesana E, Rossetti G, Ranzani V, Svendsen CN et al (2018) Faulty neuronal determination and cell polarization are reverted by modulating HD early phenotypes. Proc Natl Acad Sci U S A 115(4):E762–E771. https://doi.org/10.1073/pnas.1715865115

  31. 31.

    Koch P, Breuer P, Peitz M, Jungverdorben J, Kesavan J, Poppe D, Doerr J, Ladewig J et al (2011) Excitation-induced ataxin-3 aggregation in neurons from patients with Machado-Joseph disease. Nature 480(7378):543–546. https://doi.org/10.1038/nature10671

  32. 32.

    Eriksson M, Brown WT, Gordon LB, Glynn MW, Singer J, Scott L, Erdos MR, Robbins CM et al (2003) Recurrent de novo point mutations in lamin A cause Hutchinson-Gilford progeria syndrome. Nature 423(6937):293–298. https://doi.org/10.1038/nature01629

  33. 33.

    Meshorer E, Gruenbaum Y (2008) Rejuvenating premature aging. Nat Med 14(7):713–715. doi:nm0708-713. https://doi.org/10.1038/nm0708-713

  34. 34.

    Sieprath T, Darwiche R, De Vos WH (2012) Lamins as mediators of oxidative stress. Biochem Biophys Res Commun 421(4):635–639. https://doi.org/10.1016/j.bbrc.2012.04.058

  35. 35.

    Skoczynska A, Budzisz E, Dana A, Rotsztejn H (2015) New look at the role of progerin in skin aging. Menopause Review-Przeglad Menopauzalny 14(1):53–58. https://doi.org/10.5114/pm.2015.49532

  36. 36.

    Liu B, Wang J, Chan KM, Tjia WM, Deng W, Guan X, Huang JD, Li KM et al (2005) Genomic instability in laminopathy-based premature aging. Nat Med 11(7):780–785. https://doi.org/10.1038/nm1266

  37. 37.

    Lim RG, Salazar LL, Wilton DK, King AR, Stocksdale JT, Sharifabad D, Lau AL, Stevens B et al (2017) Developmental alterations in Huntington’s disease neural cells and pharmacological rescue in cells and mice. Nat Neurosci 20(5):648–660. https://doi.org/10.1038/nn.4532

  38. 38.

    Saudou F, Humbert S (2016) The biology of Huntingtin. Neuron 89(5):910–926. https://doi.org/10.1016/j.neuron.2016.02.003

  39. 39.

    Keryer G, Pineda JR, Liot G, Kim J, Dietrich P, Benstaali C, Smith K, Cordelieres FP et al (2011) Ciliogenesis is regulated by a huntingtin-HAP1-PCM1 pathway and is altered in Huntington disease. J Clin Investig 121(11):4372–4382. https://doi.org/10.1172/Jci57552

  40. 40.

    Saleh N, Moutereau S, Azulay JP, Verny C, Simonin C, Tranchant C, El Hawajri N, Bachoud-Levi AC et al (2010) High insulinlike growth factor I is associated with cognitive decline in Huntington disease. Neurology 75(1):57–63. https://doi.org/10.1212/WNL.0b013e3181e62076

  41. 41.

    Lopes C, Ribeiro M, Duarte AI, Humbert S, Saudou F, de Almeida LP, Hayden M, Rego AC (2014) IGF-1 intranasal administration rescues Huntington’s disease phenotypes in YAC128 mice. Mol Neurobiol 49(3):1126–1142. https://doi.org/10.1007/s12035-013-8585-5

  42. 42.

    Campos PB, Paulsen BS, Rehen SK (2014) Accelerating neuronal aging in in vitro model brain disorders: a focus on reactive oxygen species. Front Aging Neurosci 6:292. https://doi.org/10.3389/fnagi.2014.00292

  43. 43.

    Tan FCC, Hutchison ER, Eitan E, Mattson MP (2014) Are there roles for brain cell senescence in aging and neurodegenerative disorders? Biogerontology 15(6):643–660. https://doi.org/10.1007/s10522-014-9532-1

  44. 44.

    Alessio N, Capasso S, Ferone A, Di Bernardo G, Cipollaro M, Casale F, Peluso G, Giordano A et al (2017) Misidentified human gene functions with mouse models: the case of the retinoblastoma gene family in senescence. Neoplasia 19(10):781–790. https://doi.org/10.1016/j.neo.2017.06.005

  45. 45.

    Victor MB, Richner M, Hermanstyne TO, Ransdell JL, Sobieski C, Deng PY, Klyachko VA, Nerbonne JM et al (2014) Generation of human striatal neurons by microRNA-dependent direct conversion of fibroblasts. Neuron 84(2):311–323. https://doi.org/10.1016/j.neuron.2014.10.016

  46. 46.

    Victor MB, Richner M, Olsen HE, Lee SW, Monteys AM, Ma C, Huh CJ, Zhang B et al (2018) Striatal neurons directly converted from Huntington’s disease patient fibroblasts recapitulate age-associated disease phenotypes. Nat Neurosci 21(3):341–352. https://doi.org/10.1038/s41593-018-0075-7

  47. 47.

    Tang Y, Liu ML, Zang T, Zhang CL (2017) Direct reprogramming rather than ipsc-based reprogramming maintains aging hallmarks in human motor neurons. Front Mol Neurosci:10. https://doi.org/10.3389/fnmol.2017.00359

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Author information

D. Cohen-Carmon, M. Sorek, V. Lerner, Y. Yarom, and E. Meshorer designed the research; D. Cohen-Carmon, M. Sorek, V. Lerner, and M. Nissim-Rafinia performed the research; D. Cohen-Carmon, M. Sorek, and V. Lerner analyzed the data; Cohen-Carmon, M. Sorek, and E. Meshorer wrote the paper.

Correspondence to Eran Meshorer.

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The original version of this article was revised: An author named Mundackal S. Divya has been added.

Dorit Cohen-Carmon and Matan Sorek contributed equally to this work.

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Cohen-Carmon, D., Sorek, M., Lerner, V. et al. Progerin-Induced Transcriptional Changes in Huntington’s Disease Human Pluripotent Stem Cell-Derived Neurons. Mol Neurobiol (2019) doi:10.1007/s12035-019-01839-8

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Keywords

  • Progerin
  • iPS cells
  • iPSC
  • Neuronal differentiation
  • Embryonic stem cells
  • HD