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  • A patient-derived olfactory stem cell disease model for ataxia-telangiectasia

    Author(s)
    Stewart, Romal
    Kozlov, Sergei
    Matigian, Nicholas
    Wali, Gautam
    Gatei, Magtouf
    Sutharsan, Ratneswary
    Bellette, Bernadette
    Wraith-Kijas, Amanda
    Cochrane, Julie
    Coulthard, Mark
    Perry, Chris
    Sinclair, Kate
    Mackay-Sim, Alan
    Lavin, Martin F
    Griffith University Author(s)
    Mackay-Sim, Alan
    Matigian, Nicholas
    Cochrane, Julie
    Bellette, Bernadette
    Sutharsan, Ratneswary
    Wali, Gautam
    Sinclair, Kate
    Year published
    2013
    Metadata
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    Abstract
    The autosomal recessive disorder ataxia-telangiectasia (A-T) is characterized by genome instability, cancer predisposition and neurodegeneration. Although the role of ataxia-telangiectasia mutated (ATM) protein, the protein defective in this syndrome, is well described in the response to DNA damage, its role in protecting the nervous system is less clear. We describe the establishment and characterization of patient-specific stem cells that have the potential to address this shortcoming. Olfactory neurosphere (ONS)-derived cells were generated from A-T patients, which expressed stem cell markers and exhibited A-T molecular ...
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    The autosomal recessive disorder ataxia-telangiectasia (A-T) is characterized by genome instability, cancer predisposition and neurodegeneration. Although the role of ataxia-telangiectasia mutated (ATM) protein, the protein defective in this syndrome, is well described in the response to DNA damage, its role in protecting the nervous system is less clear. We describe the establishment and characterization of patient-specific stem cells that have the potential to address this shortcoming. Olfactory neurosphere (ONS)-derived cells were generated from A-T patients, which expressed stem cell markers and exhibited A-T molecular and cellular characteristics that included hypersensitivity to radiation, defective radiation-induced signaling and cell cycle checkpoint defects. Introduction of full-length ATM cDNA into these cells corrected defects in the A-T cellular phenotype. Gene expression profiling and pathway analysis revealed defects in multiple cell signaling pathways associated with ATM function, with cell cycle, cell death and DNA damage response pathways being the most significantly dysregulated. A-T ONS cells were also capable of differentiating into neural progenitors, but they were defective in neurite formation, number of neurites and length of these neurites. Thus, ONS cells are a patient-derived neural stem cell model that recapitulate the phenotype of A-T, do not require genetic reprogramming, have the capacity to differentiate into neurons and have potential to delineate the neurological defect in these patients.
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    Journal Title
    Human Molecular Genetics
    Volume
    22
    Issue
    12
    DOI
    https://doi.org/10.1093/hmg/ddt101
    Subject
    Neurosciences not elsewhere classified
    Biological Sciences
    Medical and Health Sciences
    Publication URI
    http://hdl.handle.net/10072/56947
    Collection
    • Journal articles

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