title: A patient-derived olfactory stem cell disease model for ataxia-telangiectasia.
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 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.
authors.affiliation: Queensland Institute of Medical Research, Brisbane, Queensland 4006, Australia.
authors.forename: Romal
authors.initials: R
authors.lastname: Stewart
authors.forename: Sergei
authors.initials: S
authors.lastname: Kozlov
authors.forename: Nicholas
authors.initials: N
authors.lastname: Matigian
authors.forename: Gautam
authors.initials: G
authors.lastname: Wali
authors.forename: Magtouf
authors.initials: M
authors.lastname: Gatei
authors.forename: Ratneswary
authors.initials: R
authors.lastname: Sutharsan
authors.forename: Bernadette
authors.initials: B
authors.lastname: Bellette
authors.forename: Amanda
authors.initials: A
authors.lastname: Wraith-Kijas
authors.forename: Julie
authors.initials: J
authors.lastname: Cochrane
authors.forename: Mark
authors.initials: M
authors.lastname: Coulthard
authors.forename: Chris
authors.initials: C
authors.lastname: Perry
authors.forename: Kate
authors.initials: K
authors.lastname: Sinclair
authors.forename: Alan
authors.initials: A
authors.lastname: Mackay-Sim
authors.forename: Martin F
authors.initials: MF
authors.lastname: Lavin
mesh_terms: D001260:Ataxia Telangiectasia / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D064007:Ataxia Telangiectasia Mutated Proteins / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation; D002478:Cells, Cultured; D002648:Child; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D008954:Models, Biological; D009092:Mucous Membrane; D009474:Neurons / Q000166:cytology* / Q000378:metabolism / Q000473:pathology; D009833:Olfactory Pathways / Q000166:cytology*; D010641:Phenotype; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism / Q000473:pathology
chemical_list: D064007:Ataxia Telangiectasia Mutated Proteins