Coincidence of L1 retrotransposition and DNA repair deficiency elicits synthetic lethality in S-phase mature neurons

Neurodegeneration involves the entangled processes of cell-autonomous and non-cell-autonomous neuronal cell death, which leads to a collapse in the integrity of the neural network and causes behavioral symptoms. Here, we demonstrate that aberrant cell cycle re-entry (CCR) is prominent in mature neurons and that the replication fork acts as a target site for long interspersed nuclear element-1 (L1) retrotransposition during neurodegeneration. The fatal susceptibility of S-phase neurons in 5xFAD mice is attributed to a DNA repair deficiency in response to L1-mediated replication stress. Impaired sirtuin 6 expression seems to allow stochastic L1 activation and enhanced retrotransposition. Reduced estrogen/prolactin signaling correlates well with reduced Brca1 expression that is thought to protect neurons from replication stress. Importantly, L1-mediated pathogenesis correlates well with conventional Alzheimer's disease pathology. In summary, the combination of enhanced L1 retrotransposition and DNA repair deficiency elicited synthetic lethality in S-phase neurons, highlighting a previously unknown pathogenic mechanism of neurodegeneration.