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Functional and molecular defects of hiPSC-derived neurons from patients with ATM deficiency

L Carlessi1, E Fusar Poli1, G Bechi2

  • 1Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Amadeo 42, 20133 Milano, Italy.

Cell Death & Disease
|July 18, 2014
PubMed

Insights

Ataxia telangiectasia mutated (ATM) deficiency in neurons impairs maturation and DNA repair, leading to abnormal accumulation of topoisomerase 1-DNA covalent complexes, a potential driver of neurodegeneration.

Area of Science:

  • Neuroscience
  • Genetics
  • Molecular Biology

Background:

  • Ataxia-telangiectasia (A-T) is a neurodegenerative syndrome caused by loss of ATM kinase, a crucial DNA damage response protein.
  • Understanding the molecular mechanisms of A-T neurodegeneration is essential for developing therapeutic strategies.

Purpose of the Study:

  • To investigate the impact of ATM deficiency on neuronal development, DNA damage response, and potential neurodegenerative pathways.
  • To model A-T neurodegeneration using patient-derived induced pluripotent stem cells and differentiated neurons.

Main Methods:

  • Reprogramming of patient and control fibroblasts into human-induced pluripotent stem cells (hiPSCs).
  • Differentiation of hiPSCs into neural precursor cells and subsequently into post-mitotic neurons.
  • Electrophysiological recordings, assessment of DNA double-strand break (DSB) repair, and analysis of DNA damage response markers.
  • Evaluation of apoptosis sensitivity and topoisomerase 1-DNA covalent complex (Top1-cc) accumulation.

Main Results:

  • A-T neurons exhibited normal electrophysiological properties but defective expression of neuronal maturation and synaptic markers (SCG10, SYP, PSD95).
  • A-T neurons showed impaired DSB repair and reduced phosphorylation of ATM substrates, with normal single-strand break repair.
  • A-T neurons accumulated abnormal levels of Top1-ccs and were resistant to specific genotoxic agents but not oxidative stress.

Conclusions:

  • ATM deficiency impairs neuronal maturation and DNA double-strand break repair.
  • Abnormal accumulation of Top1-ccs in A-T neurons may contribute to neurodegeneration by disrupting transcription.
  • These findings highlight a novel mechanism linking ATM deficiency, DNA repair defects, and neurodegeneration.

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