UC San Diego

Long interspersed element-1 (L1) is a retrotransposon that contributes to approximately 17% of the human genome. L1s can self-mobilize by retrotransposition using their reverse transcriptase and integrate in a new region in the genome. Increased L1 activity is associated with Rett Syndrome (RTT), a neurological disorder that arises due to a mutation in the methyl-CpG-binding protein 2 (MECP2) gene. Affected individuals develop seizures, microcephaly, and a regression in motor function and developmental skills. MeCP2 is known to represses L1 expression, however when MeCP2 is absent, like in individuals with RTT, L1 retrotransposition increases. To model the role L1 has on RTT neuropathology, we used induced pluripotent stem cells (iPSCs) to generate human cortical neurons. We show that L1 retrotransposition plays a role in the abnormal neuronal morphology and decreased synaptogenesis seen in RTT. Furthermore, chronic treatment with reverse-transcriptase inhibitors (RTis), known for limiting L1 activity, shows a rescue of these phenotypes. We also utilized iPSCs to generate 3D neurospheres and cortical organoids to better mimic neuronal architecture and investigate L1’s role in synaptogenesis. In RTT cells, we report a significant decrease in neural activity that is improved when treated with RTis. Additionally, RTT organoids exhibited a microcephaly-like reduction in size that was rescued with chronic treatment of RTis. Our results demonstrate that L1 plays a role in the altered neuronal phenotypes seen in RTT and is one of many contributors to the pathophysiology of this disorder.