Table 6 Hypotheses to Explain the Neurodegeneration in A-T

• 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 [186–189]

  o aneuploidy [190]

• Defective response to oxidative stress characterized by elevated ROS and altered cellular redox status

[191–194] and reviewed in [11, 195, 196]

• Mitochondrial dysfunction [197–199] 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 [201–203]

  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]