Functional and molecular defects of hiPSC-derived neurons from patients with ATM deficiency (Articolo in rivista)

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  • Functional and molecular defects of hiPSC-derived neurons from patients with ATM deficiency (Articolo in rivista) (literal)
Anno
  • 2014-01-01T00:00:00+01:00 (literal)
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#doi
  • 10.1038/cddis.2014.310 (literal)
Alternative label
  • Carlessi, L.; Poli, E. Fusar; Bechi, G.; Mantegazza, M.; Pascucci, B.; Narciso, L.; Dogliotti, E.; Sala, C.; Verpelli, C.; Lecis, D.; Delia, D. (2014)
    Functional and molecular defects of hiPSC-derived neurons from patients with ATM deficiency
    in Cell death and disease
    (literal)
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#autori
  • Carlessi, L.; Poli, E. Fusar; Bechi, G.; Mantegazza, M.; Pascucci, B.; Narciso, L.; Dogliotti, E.; Sala, C.; Verpelli, C.; Lecis, D.; Delia, D. (literal)
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#numeroVolume
  • 5 (literal)
Rivista
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  • 14 (literal)
Note
  • ISI Web of Science (WOS) (literal)
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  • Fondazione IRCCS Istituto Nazionale Tumori Milan; Istituto Nazionale Neurologico C. Besta; Centre National de la Recherche Scientifique (CNRS); Universite Nice Sophia Antipolis; Consiglio Nazionale delle Ricerche (CNR); Istituto Superiore di Sanita'; Istituto Superiore di Sanita'; Consiglio Nazionale delle Ricerche (CNR); Dept Biotechnol & Translat Med (literal)
Titolo
  • Functional and molecular defects of hiPSC-derived neurons from patients with ATM deficiency (literal)
Abstract
  • Loss of ataxia telangiectasia mutated (ATM) kinase, a key factor of the DNA damage response (DDR) pathway, causes the cancer predisposing and neurodegenerative syndrome ataxia-telangiectasia (A-T). To investigate the mechanisms of neurodegeneration, we have reprogrammed fibroblasts from ATM-null A-T patients and normal controls to pluripotency (human-induced pluripotent stem cells), and derived from these neural precursor cells able to terminally differentiate into post-mitotic neurons positive to >90% for beta-tubulin III + /microtubule-associated protein 2 +. We show that A-T neurons display similar voltage-gated potassium and sodium currents and discharges of action potentials as control neurons, but defective expression of the maturation and synaptic markers SCG10, SYP and PSD95 (postsynaptic density protein 95). A-T neurons exhibited defective repair of DNA double-strand breaks (DSBs) and repressed phosphorylation of ATM substrates (e.g., gamma H2AX, Smc1-S966, Kap1-S824, Chk2-T68, p53-S15), but normal repair of single-strand breaks, and normal short-and long-patch base excision repair activities. Moreover, A-T neurons were resistant to apoptosis induced by the genotoxic agents camptothecin and trabectedin, but as sensitive as controls to the oxidative agents. Most notably, A-T neurons exhibited abnormal accumulation of topoisomerase 1-DNA covalent complexes (Top1-ccs). These findings reveal that ATM deficiency impairs neuronal maturation, suppresses the response and repair of DNA DSBs, and enhances Top1-cc accumulation. Top1-cc could be a risk factor for neurodegeneration as they may interfere with transcription elongation and promote transcriptional decline. (literal)
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