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Biochemistry (Moscow)

, Volume 83, Issue 9, pp 1040–1045 | Cite as

Genome Editing and the Problem of Tetraploidy in Cell Modeling of the Genetic Form of Parkinsonism

  • V. V. Simonova
  • A. S. Vetchinova
  • E. V. Novosadova
  • L. G. Khaspekov
  • S. N. IllarioshkinEmail author
Mini-Review

Abstract

The prevalent form of familial parkinsonism is caused by mutations in the LRRK2 gene encoding for the mitochondrial protein kinase. In the review, we discuss possible causes of appearance of tetraploid cells in neuronal precursors obtained from induced pluripotent stem cells from patients with the LRRK2-associated form of parkinsonism after genome editing procedure. As LRRK2 protein participates in cell proliferation and maintenance of the nuclear envelope, spindle fibers, and cytoskeleton, mutations in the LRRK2 gene can affect protein functions and lead, via various mechanisms, to the mitotic machinery disintegration and chromosomal aberration. These abnormalities can appear at different stages of fibroblast reprogramming; therefore, editing of the LRRK2 nucleotide sequence should be done during or before the reprogramming stage.

Keywords

parkinsonism LRRK2 induced pluripotent stem cells neuronal precursors genome editing tetraploidy 

Abbreviations

ATM

ataxia telangiectasia mutated

iPSCs

induced pluripotent stem cells

PD

Parkinson’s disease

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References

  1. 1.
    De Lau, L. M. L., and Breteler, M. M. B. (2006) Epidemiology of Parkinson’s disease, Lancet Neurol., 5, 525–535.CrossRefPubMedGoogle Scholar
  2. 2.
    Hernandez, D. G., Reed, X., and Singleton, A. B. (2016) Genetics in Parkinson disease: Mendelian versus non-Mendelian inheritance, J. Neurochem., 139 (Suppl. 1), 59–74.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Singleton, A. B., Farrer, M. J., and Bonifati, V. (2013) The genetics of Parkinson’s disease: progress and therapeutic implications, Mov. Disord., 28, 14–23.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Poewe, W., Seppi, K., and Tanner, C. M. (2017) Parkinson disease, Nat. Rev. Dis. Primers, 3, 17013.CrossRefPubMedGoogle Scholar
  5. 5.
    Jenner, P., Morris, H. R., Robbins, T. W., Goedert, M., Hardy, J., Ben-Shlomo, Y., Bolam, P., Burn, D., Hindle, J. V., and Brooks, D. (2013) Parkinson’s disease-the debate on the clinical phenomenology, etiology, pathology and pathogenesis, J. Parkinson’s Dis., 3, 1–11.Google Scholar
  6. 6.
    Kang, J. F., Tang, B. S., and Guo, J. F. (2016) The progress of induced pluripotent stem cells as models of Parkinson’s disease, Stem Cells Int., 2016, 4126214.PubMedPubMedCentralGoogle Scholar
  7. 7.
    Holmqvist, S., Lehtonen, S., Chumarina, M., Puttonen, K. A., Azevedo, C., Lebedeva, O., Ruponen, M., Oksanen, M., Djelloul, M., Collin, A., Goldwurm, S., Meyer, M., Lagarkova, M., Kiselev, S., Koistinaho, J., and Roybon, L. (2016) Creation of a library of induced pluripotent stem cells from Parkinsonian patients, NPJ Parkinson’s Dis., 2, 16009.CrossRefGoogle Scholar
  8. 8.
    Illarioshkin, S. N., Khaspekov, L. G., and Grivennikov, I. A. (2017) Modeling of Parkinson’s Disease with Induced Pluripotent Stem Cells [in Russian], ZAO RKI Sovero Press, Moscow.Google Scholar
  9. 9.
    Hargus, G., Cooper, O., Deleidi, M., Levy, A., Lee, K., Marlow, E., Yow, A., Soldner, F., Hockemeyer, D., Hallett, P. J., Osborn, T., Jaenisch, R., and Isacson, O. (2010) Differentiated Parkinson patient-derived induced pluripotent cells grow in the adult rodent brain and reduce motor asymmetry in Parkinsonian rats, Proc. Natl. Acad. Sci. USA, 107, 15921–15926.CrossRefPubMedGoogle Scholar
  10. 10.
    Cornu, T., Mussolino, C., and Cathomen, T. (2017) Refining strategies to translate genome editing to the clinic, Nature Med., 23, 415–423.CrossRefPubMedGoogle Scholar
  11. 11.
    Healy, D. G., Falchi, M., O’Sullivan, S. S., Bonifati, V., Durr, A., Bressman, S., Brice, A., Aasly, J., Zabetian, C. P., Goldwurm, S., Ferreira, J. J., Tolosa, E., Kay, D. M., Klein, C., Williams, D. R., Marras, C., Lang, A. E., Wszolek, Z. K., Berciano, J., Schapira, A. H., Lynch, T., Bhatia, K. P., Gasser, T., Lees, A. J., and Wood, N. W. (2008) International LRRK2 Consortium. Phenotype, genotype, and worldwide genetic penetrance of LRRK2-associated Parkinson’s disease: a case-control study, Lancet Neurol., 7, 583–590.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Dachsel, J. C., Behrouz, B., Yue, M., Beevers, J. E., Melrose, H. L., and Farrer, M. J. (2010) A comparative study of LRRK2 function in primary neuronal cultures, Parkinsonism Relat. Disord., 16, 650–655.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Tong, Y., Giaime, E., Yamaguchi, H., Ichimura, T., Liu, Y., Si, H., Cai, H., Bonventre, J. V., and Shen, J. (2012) Loss of leucine-rich repeat kinase 2 causes age-dependent biphasic alterations of the autophagy pathway, Mol. Neurodegener., 7,2.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Vetchinova, A. S., Simonova, V. V., Novosadova, E. V., Manuilova, E. S., Nenasheva, V. V., Tarantul, V. Z., Grivennikov, I. A., Khaspekov, L. G., and Illarioshkin, S. N. (2018) Cytogenetic analysis of results of the genome editing on the cell model of the Parkinson’s disease, Byul. Eksp. Biol. Med., 3, 355–359.Google Scholar
  15. 15.
    Cong, L., Ran, F. A., Cox, D., Lin, S., Barretto, R., Habib, N., Hsu, P. D., Wu, X., Jiang, W., Marraffini, L. A., and Zhang, F. (2013) Multiplex genome engineering using CRISPR/Cas systems, Science, 339, 819–823.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Vasil’eva, E. A., Melino, D., and Barlev, N. A. (2015) Application of the directed genomic editing system CRISPR/Cas to pluripotent stem cells, Tsitologiya, 1, 19–30.Google Scholar
  17. 17.
    Zanet, J., Freije, A., Ruiz, M., Coulon, V., Sanz, J. R., Chiesa, J., and Gandarillas, A. (2010) A mitosis block links active cell cycle with human epidermal differentiation and results in endoreplication, PLoS One, 5, e15701.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Davoli, T., and de Lange, T. (2011) The causes and consequences of polyploidy in normal development and cancer, Annu. Rev. Cell Dev. Biol., 27, 585–610.CrossRefPubMedGoogle Scholar
  19. 19.
    Mosch, B., Morawski, M., Mittag, A., Lenz, D., Tarnok, A., and Arendt, T. (2007) Aneuploidy and DNA replication in the normal human brain and Alzheimer’s disease, J. Neurosci., 27, 6859–6867.CrossRefPubMedGoogle Scholar
  20. 20.
    Frade, J. M. (2010) Somatic tetraploidy in vertebrate neurons: implications in physiology and pathology, Commun. Integr. Biol., 3, 201–203.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Ganem, N. J., Storchova, Z., and Pellman, D. (2007) Tetraploidy: aneuploidy and cancer, Curr. Opin. Genet. Dev., 17, 157–162.CrossRefPubMedGoogle Scholar
  22. 22.
    Joglekar, A. P. (2016) A cell biological perspective on past, present and future investigations of the spindle assembly checkpoint, Biology (Basel), 5, E44.Google Scholar
  23. 23.
    Holland, A. J., and Cleveland, D. W. (2012) Losing balance: the origin and impact of aneuploidy in cancer, EMBO Rep., 13, 501–514.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Marechal, A., and Zou, L. (2013) DNA damage sensing by the ATM and ATR kinases, Cold Spring Harb. Perspect. Biol., 5, a012716.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Davoli, T., Denchi, E. L., and de Lange, T. (2010) Persistent telomere damage induces bypass of mitosis and tetraploidy, Cell, 41, 81–93.CrossRefGoogle Scholar
  26. 26.
    Chen, Z., Cao, Z., Zhang, W., Gu, M., Dong Zhou, Z., Li, B., Li, J., King Tan, E., and Zeng, L. (2017) LRRK2 interacts with ATM and regulates Mdm2-p53 cell proliferation axis in response to genotoxic stress, Hum. Mol. Genet., 26, 4494–4505.CrossRefPubMedGoogle Scholar
  27. 27.
    Kemp, K., Wilkins, A., and Scolding, N. (2014) Cell fusion in the brain: two cells forward, one cell back, Acta Neuropathol., 128, 629–638.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Coskun, P. E., and Busciglio, J. (2012) Oxidative stress and mitochondrial dysfunction in Down’s syndrome: relevance to aging and dementia, Curr. Gerontol. Geriatr. Res., 2012, 383170.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Greaves, L. C., Reeve, A. K., Taylor, R. W., and Turnbul, D. M. (2012) Mitochondrial DNA and disease, J. Pathol., 226, 274–286.CrossRefPubMedGoogle Scholar
  30. 30.
    Sanders, L. H., Laganiere, J., Cooper, O., Mak, S. K., Vu, B. J., Huang, Y. A., Paschon, D. E., Vangipuram, M., Sandarajan, R., Urnov, F. D., Langston, J. W., Gregory, P. D., Zhang, H. S., Greenamyre, J. T., Isacson, O., and Schule, B. (2014) LRRK2 mutations cause mitochondrial DNA damage in iPS-derived neural cells from Parkinson’s disease patients: reversal by gene correction, Neurobiol. Dis., 62, 381–386.CrossRefPubMedGoogle Scholar
  31. 31.
    Gentric, G., Maillet, V., Paradis, V., Couton, D., L’Hermitte, A., Panasyuk, G., Fromenty, B., Celton-Morizur, S., and Desdouets, C. (2015) Oxidative stress promotes pathologic polyploidization in nonalcoholic fatty liver disease, J. Clin. Invest., 125, 981–992.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Dephoure, N., Hwang, S., O’Sullivan, C., Dodgson, S. E., Gygi, S. P., Amon, A., and Torres, E. M. (2014) Quantitative proteomic analysis reveals post-translational responses to aneuploidy in yeast, Elife, 3, e03023.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Orenstein, S. J., Kuo, S.-H., Tasset, I., Arias, E., Koga, H., Fernandez-Carasa, I., Cortes, E., Honig, L. S., Dauer, W., Consiglio, A., Raya, A., Sulzer, D., and Cuervo, A. M. (2013) Interplay of LRRK2 with chaperone-mediated autophagy, Nat. Neurosci., 16, 394–406.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Nguyen, H. N., Byers, B., Cord, B., Shcheglovitov, A., Byrne, J., Gujar, P., Kee, K., Schule, B., Dolmetsch, R. E., Langston, W., Palmer, T. D., and Pera, R. R. (2011) LRRK2 mutant iPSC-derived DA neurons demonstrate increased susceptibility to oxidative stress, Cell Stem Cell, 8, 267–280.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Cooper, O., Seo, H., Andrabi, S., Guardia-Laguarta, C., Graziotto, J., Sundberg, M., McLean, J. R., Carrillo-Reid, L., Xie, Z., Osborn, T., Hargus, G., Deleidi, M., Lawson, T., Bogetofte, H., Perez-Torres, E., Clark, L., Moskowitz, C., Mazzulli, J., Chen, L., Volpicelli-Daley, L., Romero, N., Jiang, H., Uitti, R. J., Huang, Z., Opala, G., Scarffe, L. A., Dawson, V. L., Klein, C., Feng, J., Ross, O. A., Trojanowski, J. Q., Lee, V. M., Marder, K., Surmeier, D. J., Wszolek, Z. K., Przedborski, S., Krainc, D., Dawson, T. M., and Isacson, O. (2012) Pharmacological rescue of mitochondrial deficits in iPSC-derived neural cells from patients with familial Parkinson’s disease, Sci. Transl. Med., 4, 141ra90.CrossRefGoogle Scholar
  36. 36.
    Padlesnig, P., Vilas, D., Taylor, P., Shaw, L. M., Tolosa, E., and Trullas, R. (2016) Mitochondrial DNA in CSN distinguishes LRRK2 from idiopathic Parkinson’s disease, Neurobiol. Dis., 94, 10–17.CrossRefGoogle Scholar
  37. 37.
    Ho, C. Y., and Lammerding, J. (2012) Lamins at a glance, J. Cell Sci., 125, 2087–2093.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Gonzalo, S. (2014) DNA damage and lamins, Adv. Exp. Med. Biol., 773, 377–399.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Liu, G.-H., Qu, J., Suzuki, K., Nive, E., Li, M., Montserrat, N., Yi, F., Xu, X., Ruiz, S., Zhang, W., Wagner, U., Kim, A., Ren, B., Li, Y., Goebl, A., Kim, J., Soligalla, R. D., Dubova, I., Thompson, J., Yates, J., 3rd, Esteban, C. R., Sancho-Martinez, I., and Belmonte, J. C. I. (2012) Progressive degeneration of human neural stem cells caused by pathogenic LRRK2 mutations, Nature, 491, 603–607.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    McClatchey, A. I. (2014) ERM proteins at a glance, J. Cell Sci., 127, 3199–3204.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Gandhi, P. N., Wang, X., Zhu, X., Chen, S. G., and Wilson-Delfosse, A. L. (2008) The Roc domain of leucinerich repeat kinase 2 is sufficient for interaction with micro-tubules, J. Neurosci. Res., 86, 1711–1720.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Gillardon, F. (2009) Leucine-rich repeat kinase 2 phospho-rylates brain tubulin-beta isoforms and modulates micro-tubule stability - a point of convergence in parkinsonian neurodegeneration? J. Neurochem., 110, 1514–1522.CrossRefPubMedGoogle Scholar
  43. 43.
    Parisiadou, L., and Cai, H. (2010) LRRK2 function on actin and microtubule dynamics in Parkinson disease, Commun. Integr. Biol., 3, 396–400.CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Agalliu, I., San Luciano, M., Mirelman, A., Giladi, N., Waro, B., Aasly, J., Inzelberg, R., Hassin-Baer, S., Friedman, E., Ruiz-Martinez, J., Marti-Masso, J. F., Orr-Urtreger, A., Bressman, S., and Saunders-Pullman, R. (2015) Higher frequency of certain cancers in LRRK2 G2019S mutation carriers with Parkinson’s disease: a pooled analysis, JAMA Neurol., 72, 58–65.CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Saunders-Pullman, R., Barrett, M. J., Stanley, K., Luciano, M. S., Shanker, V., Severt, L., Hunt, A., Raymond, D., Ozelius, L. J., and Bressman, S. B. (2010) LRRK2 G2019S mutations are associated with an increased cancer risk in Parkinson disease, Mov. Disord., 25, 2536–2541.CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Nichols, R. J., Dzamko, N., Hutti, J. E., Cantley, L. C., Deak, M., Moran, J., Bamborough, P., Reith, A. D., and Alessi, D. R. (2009) Substrate specificity and inhibitors of LRRK2, a protein kinase mutated in Parkinson’s disease, Biochem. J., 424, 47–60.CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Liou, G. Y., and Gallo, K. A. (2009) New biochemical approaches towards understanding the Parkinson’s disease-associated kinase, LRRK2, Biochem. J., 424, 1–3.CrossRefGoogle Scholar
  48. 48.
    Lee, S.-Y., and Chung, S.-K. (2016) Integrating gene correction in the reprogramming and transdifferentiation processes: a one-step strategy to overcome stem cell-based gene therapy limitations, Stem Cells Intern., 2016, 2725670.Google Scholar
  49. 49.
    Dekel-Naftali, M., Aviram-Goldring, A., Litmanovich, T., Shamash, J., Reznik-Wolf, H., Laevsky, I., Amit, M., Itskovitz-Eldor, J., Yung, Y., Hoyrvitz, A., Schiff, E., and Rienstein, S. (2012) Screening of human pluripotent stem cells using CGH and FISH reveals low-grade mosaic aneuploidy and a recurrent amplification of chromosome 1q, Eur. J. Hum. Genet., 20, 1248–1255.CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Gore, A., Li, Z., Fung, H.-L., Young, J. E., Agarwal, S., Antosiewicz-Bourget, J., Canto, I., Giorgetti, A., Israel, M. A., Kiskinis, E., Lee, J. H., Loh, Y. H.,, Manos, P. D., Montserrat, N., Panopoulos, A. D., Ruiz, S., Wilbert, M. L., Yu, J., Kirkness, E. F., Izpisua Belmonte, J. C., Rossi, D. J., Thomson, J. A., Eggan, K., Daley, G. Q., Goldstein, L. S., and Zhang, K. (2011) Somatic coding mutation in human induced pluripotent stem cells, Nature, 471, 63–67.CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Hussein, S. M., Batada, N. N., Vuoristo, S., Ching, R. W., Autio, R., Narva, E., Ng, S., Sourour, M., Hamalainen, R., Olsson, C., Lundin, K., Mikkola, M., Trokovic, R., Peitz, M., Brustle, O., Bazett-Jones, D. P., Alitalo, K., Lahesmaa, R., Nagy, A., and Otonkoski, T. (2012) Copy number variation and selection during reprogramming to pluripotency, Nature, 471, 58–62.CrossRefGoogle Scholar

Copyright information

© Pleiades Publishing, Ltd. 2018

Authors and Affiliations

  • V. V. Simonova
    • 1
  • A. S. Vetchinova
    • 1
  • E. V. Novosadova
    • 2
  • L. G. Khaspekov
    • 1
  • S. N. Illarioshkin
    • 1
    Email author
  1. 1.Research Center of NeurologyMoscowRussia
  2. 2.Institute of Molecular GeneticsRussian Academy of SciencesMoscowRussia

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