Differential gene expression analysis in S-phase neurons derived from L1-GFP/5xFAD and L1-GFP mice

Neurodegeneration involves entangled processes of neuronal autonomous and non-neuronal autonomous death, which leads to a collapse in the integrity of the neural network and causes behavioral symptoms. Here, we demonstrate that aberrant cell cycle reentry (CCR) is prominent in mature neurons and the replication fork in S-phase neurons acts as a target site for retrotransposition by long interspersed nuclear element-1 (L1) in neurodegeneration-prone 5xFAD mice. Interestingly, the morbid susceptibility of S-phase neurons to cell death has been attributed to enhanced L1 retrotransposition and DNA repair deficiency. Furthermore, deficit in sirtuin 6 expression and estrogen/prolactin signaling promote stochastic L1 retrotransposition and impair Brca1 expression in S-phase neurons, respectively. Importantly, L1 retrotransposition-related neuronal malfunction is correlated with conventional AD pathology. Current data suggest that the coincidence of enhanced L1 retrotransposition and DNA repair deficiency causes synthetic lethality in S-phase neurons, providing a previously unknown pathogenic mechanism of neurodegeneration.