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Table 6 Hypotheses to Explain the Neurodegeneration in A-T

From: Ataxia telangiectasia: a review

• Defective DDR [183, 184] or repair resulting in:
o the failed clearance of genomically damaged neurons during development [76, 185]
o transcription stress [119] and abortive transcription involving topoisomerase 1 cleavage complex (TOP1cc) dependent lesions [186189]
o aneuploidy [190]
• Defective response to oxidative stress characterized by elevated ROS and altered cellular redox status
[191194] and reviewed in [11, 195, 196]
• Mitochondrial dysfunction [197199] and reviewed in [11]
• Defects in neuronal function involving:
o Failed cell cycle regulation resulting in the re-entry of post-mitotic (mature) neurons into the cell cycle [200]
o Synaptic/vesicular dysregulation [201203]
o Altered epigenetics including
  − HDAC4 nuclear translocation [204]
  − Histone H3 hypermethylation [205] and
  − Reduced 5-hydroxymethylcytosine [206]
• Defects in brain vasculature [207]
• Altered protein turnover [208]
  1. DDR DNA damage response