ATM Kinase pp 391-400 | Cite as

A Patient-Specific Stem Cell Model to Investigate the Neurological Phenotype Observed in Ataxia-Telangiectasia

  • Romal Stewart
  • Gautam Wali
  • Chris Perry
  • Martin F. Lavin
  • Francois Féron
  • Alan Mackay-Sim
  • Ratneswary SutharsanEmail author
Part of the Methods in Molecular Biology book series (MIMB, volume 1599)


The molecular pathogenesis of ataxia-telangiectasia (A-T) is not yet fully understood, and a versatile cellular model is required for in vitro studies. The occurrence of continuous neurogenesis and easy access make the multipotent adult stem cells from the olfactory mucosa within the nasal cavity a potential cellular model. We describe an efficient method to establish neuron-like cells from olfactory mucosa biopsies derived from A-T patients for the purpose of studying the cellular and molecular aspects of this debilitating disease.

Key words

Ataxia-telangiectasia Olfactory mucosa Stem cells Neuronal differentiation 



This work was supported by funding from the Australian Department of Health and Ageing to AMS and the National Health and Medical Research Council (NHMRC) to MFL. We thank A-T patients and their families for their support. Support and help of BrAshA-T charity ( are gratefully acknowledged as well as clinicians and nurses of the Australian A-T Clinic for patient recruitment and biopsies.


  1. 1.
    Boder E (1985) Ataxia-telangiectasia: an overview. Kroc Found Ser 19:1–63PubMedGoogle Scholar
  2. 2.
    Lavin MF (2008) Ataxia-telangiectasia: from a rare disorder to a paradigm for cell signalling and cancer. Nat Rev Mol Cell Biol 9(10):759–769. doi: 10.1038/nrm2514 CrossRefPubMedGoogle Scholar
  3. 3.
    Bhatti S, Kozlov S, Farooqi AA, Naqi A, Lavin M, Khanna KK (2011) ATM protein kinase: the linchpin of cellular defenses to stress. Cell Mol Life Sci 68(18):2977–3006CrossRefPubMedGoogle Scholar
  4. 4.
    McKinnon PJ (2012) ATM and the molecular pathogenesis of ataxia telangiectasia. Ann Rev Pathol Mech Dis 7:303–321CrossRefGoogle Scholar
  5. 5.
    Lavin MF (2013) The appropriateness of the mouse model for ataxia-telangiectasia: neurological defects but no neurodegeneration. DNA Repair 12(8):612–619CrossRefPubMedGoogle Scholar
  6. 6.
    Murrell W, Bushell GR, Livesey J, McGrath J, MacDonald KP, Bates PR, Mackay-Sim A (1996) Neurogenesis in adult human. Neuroreport 7(6):1189–1194CrossRefPubMedGoogle Scholar
  7. 7.
    Murrell W, Feron F, Wetzig A, Cameron N, Splatt K, Bellette B, Bianco J, Perry C, Lee G, Mackay-Sim A (2005) Multipotent stem cells from adult olfactory mucosa. Dev Dyn 233(2):496–515. doi: 10.1002/dvdy.20360 CrossRefPubMedGoogle Scholar
  8. 8.
    Abrams MT, Kaufmann WE, Rousseau F, Oostra BA, Wolozin B, Taylor CV, Lishaa N, Morel M-L, Hoogeveen A, Reiss AL (1999) FMR1 gene expression in olfactory neuroblasts from two males with fragile X syndrome. Am J Med Genet 82(1):25–30CrossRefPubMedGoogle Scholar
  9. 9.
    Arnold SE, Han L-Y, Moberg PJ, Turetsky BI, Gur RE, Trojanowski JQ, Hahn C-G (2001) Dysregulation of olfactory receptor neuron lineage in schizophrenia. Arch Gen Psychiatry 58(9):829–835CrossRefPubMedGoogle Scholar
  10. 10.
    English J, Fan Y, Föcking M, Lopez L, Hryniewiecka M, Wynne K, Dicker P, Matigian N, Cagney G, Mackay-Sim A (2015) Reduced protein synthesis in schizophrenia patient-derived olfactory cells. Transl Psychiatry 5(10):e663CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Fan Y, Abrahamsen G, McGrath JJ, Mackay-Sim A (2012) Altered cell cycle dynamics in schizophrenia. Biol Psychiatry 71(2):129–135. doi: 10.1016/j.biopsych.2011.10.004 CrossRefPubMedGoogle Scholar
  12. 12.
    Fan Y, Abrahamsen G, Mills R, Calderón CC, Tee JY, Leyton L, Murrell W, Cooper-White J, McGrath JJ, Mackay-Sim A (2013) Focal adhesion dynamics are altered in schizophrenia. Biol Psychiatry 74(6):418–426CrossRefPubMedGoogle Scholar
  13. 13.
    Féron F, Perry C, Hirning M, McGrath J, Mackay-Sim A (1999) Altered adhesion, proliferation and death in neural cultures from adults with schizophrenia. Schizophr Res 40(3):211–218CrossRefPubMedGoogle Scholar
  14. 14.
    Matigian N, Abrahamsen G, Sutharsan R, Cook AL, Vitale AM, Nouwens A, Bellette B, An J, Anderson M, Beckhouse AG, Bennebroek M, Cecil R, Chalk AM, Cochrane J, Fan Y, Feron F, McCurdy R, McGrath JJ, Murrell W, Perry C, Raju J, Ravishankar S, Silburn PA, Sutherland GT, Mahler S, Mellick GD, Wood SA, Sue CM, Wells CA, Mackay-Sim A (2010) Disease-specific, neurosphere-derived cells as models for brain disorders. Dis Model Mech 3(11-12):785–798. doi: 10.1242/dmm.005447 CrossRefPubMedGoogle Scholar
  15. 15.
    Ronnett GV, Leopold D, Cai X, Hoffbuhr KC, Moses L, Hoffman EP, Naidu S (2003) Olfactory biopsies demonstrate a defect in neuronal development in Rett's syndrome. Ann Neurol 54(2):206–218CrossRefPubMedGoogle Scholar
  16. 16.
    Cook AL, Vitale AM, Ravishankar S, Matigian N, Sutherland GT, Shan J, Sutharsan R, Perry C, Silburn PA, Mellick GD (2011) NRF2 activation restores disease related metabolic deficiencies in olfactory neurosphere-derived cells from patients with sporadic Parkinson's disease. PLoS One 6(7):e21907CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Arnold SE, Lee EB, Moberg PJ, Stutzbach L, Kazi H, Han LY, Lee VM, Trojanowski JQ (2010) Olfactory epithelium amyloid-β and paired helical filament-tau pathology in Alzheimer disease. Ann Neurol 67(4):462–469CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Wolozin B, Lesch P, Lebovics R, Sunderland T (1993) Olfactory neuroblasts from Alzheimer donors: studies on APP processing and cell regulation. Biol Psychiatry 34(12):824–838CrossRefPubMedGoogle Scholar
  19. 19.
    Abrahamsen G, Fan Y, Matigian N, Wali G, Bellette B, Sutharsan R, Raju J, Wood SA, Veivers D, Sue CM, Mackay-Sim A (2013) A patient-derived stem cell model of hereditary spastic paraplegia with SPAST mutations. Dis Model Mech 6(2):489–502. doi: 10.1242/dmm.010884 CrossRefPubMedGoogle Scholar
  20. 20.
    Fan Y, Wali G, Sutharsan R, Bellette B, Crane DI, Sue CM, Mackay-Sim A (2014) Low dose tubulin-binding drugs rescue peroxisome trafficking deficit in patient-derived stem cells in hereditary spastic paraplegia. Biol Open 3(6):494–502CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Boone N, Loriod B, Bergon A, Sbai O, Formisano-Treziny C, Gabert J, Khrestchatisky M, Nguyen C, Feron F, Axelrod FB, Ibrahim EC (2010) Olfactory stem cells, a new cellular model for studying molecular mechanisms underlying familial dysautonomia. PLoS One 5(12):e15590. doi: 10.1371/journal.pone.0015590 CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Ghanbari HA, Ghanbari K, Harris PL, Jones PK, Kubat Z, Castellani RJ, Wolozin BL, Smith MA, Perry G (2004) Oxidative damage in cultured human olfactory neurons from Alzheimer's disease patients. Aging Cell 3(1):41–44CrossRefPubMedGoogle Scholar
  23. 23.
    McCurdy RD, Féron F, Perry C, Chant DC, McLean D, Matigian N, Hayward NK, McGrath JJ, Mackay-Sim A (2006) Cell cycle alterations in biopsied olfactory neuroepithelium in schizophrenia and bipolar I disorder using cell culture and gene expression analyses. Schizophr Res 82(2):163–173CrossRefPubMedGoogle Scholar
  24. 24.
    Stewart R, Kozlov S, Matigian N, Wali G, Gatei M, Sutharsan R, Bellette B, Wraith-Kijas A, Cochrane J, Coulthard M, Perry C, Sinclair K, Mackay-Sim A, Lavin MF (2013) A patient-derived olfactory stem cell disease model for ataxia-telangiectasia. Hum Mol Genet 22(12):2495–2509. doi: 10.1093/hmg/ddt101 CrossRefPubMedGoogle Scholar
  25. 25.
    Mar JC, Matigian NA, Mackay-Sim A, Mellick GD, Sue CM, Silburn PA, McGrath JJ, Quackenbush J, Wells CA (2011) Variance of gene expression identifies altered network constraints in neurological disease. PLoS Genet 7(8):e1002207CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Féron F, Perry C, Girard SD, Mackay-Sim A (2013) Isolation of adult stem cells from the human olfactory mucosa. Methods Mol Biol 1059:107–114CrossRefPubMedGoogle Scholar
  27. 27.
    Girard SD, Devéze A, Nivet E, Gepner B, Roman FS, Féron F (2011) Isolating nasal olfactory stem cells from rodents or humans. J Vis Exp 54:2762. doi: 10.3791/2762 Google Scholar

Copyright information

© Springer Science+Business Media LLC 2017

Authors and Affiliations

  • Romal Stewart
    • 1
  • Gautam Wali
    • 2
  • Chris Perry
    • 3
  • Martin F. Lavin
    • 7
  • Francois Féron
    • 4
    • 5
  • Alan Mackay-Sim
    • 2
  • Ratneswary Sutharsan
    • 2
    • 6
    Email author
  1. 1.University of Queensland Centre for Clinical ResearchBrisbaneAustralia
  2. 2.Eskitis Institute for Drug DiscoveryGriffith UniversityNathanAustralia
  3. 3.Department of Otolaryngology Head and Neck SurgeryPrincess Alexandra HospitalBrisbaneAustralia
  4. 4.Aix Marseille Université, CNRS, NICN, UMR7259MarseilleFrance
  5. 5.APHM, Centre d’Investigations Cliniques en BiothérapieMarseilleFrance
  6. 6.Griffith Institute for Drug Discovery (GRIDD)Griffith UniversityNathanAustralia
  7. 7.University of Queensland Centre for Clinical Research (UQCCR), University of Queensland, HerstonBrisbaneAustralia

Personalised recommendations