Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Human Neuron Core, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Cell Rep. 2023 Aug 29;42(8):112838. doi: 10.1016/j.celrep.2023.112838. Epub 2023 Jul 25.
Autism spectrum disorder (ASD) is a highly prevalent neurodevelopmental disorder, but new therapies have been impeded by a lack of understanding of the pathological mechanisms. Tuberous sclerosis complex (TSC) and fragile X syndrome are associated with alterations in the mechanistic target of rapamycin (mTOR) and fragile X messenger ribonucleoprotein 1 (FMRP), which have been implicated in the development of ASD. Previously, we observed that transcripts associated with FMRP were down-regulated in TSC2-deficient neurons. In this study, we find that FMRP turnover is dysregulated in TSC2-deficient rodent primary neurons and human induced pluripotent stem cell (iPSC)-derived neurons and is dependent on the E3 ubiquitin ligase anaphase-promoting complex. We also demonstrate that overexpression of FMRP can partially rescue hyperexcitability in TSC2-deficient iPSC-derived neurons. These data indicate that FMRP dysregulation represents an important pathological mechanism in the development of abnormal neuronal activity in TSC and illustrate a molecular convergence between these two neurogenetic disorders.
自闭症谱系障碍（ASD）是一种高发的神经发育障碍，但由于缺乏对病理机制的理解，新的治疗方法一直受到阻碍。结节性硬化症（TSC）和脆性 X 综合征与雷帕霉素靶蛋白（mTOR）和脆性 X 信使核糖核蛋白 1（FMRP）的机制靶点的改变有关，这些改变与 ASD 的发展有关。此前，我们观察到与 FMRP 相关的转录本在 TSC2 缺陷神经元中下调。在这项研究中，我们发现在 TSC2 缺陷的啮齿动物原代神经元和人诱导多能干细胞（iPSC）衍生神经元中，FMRP 的周转受到失调，并且依赖于 E3 泛素连接酶有丝分裂促进复合物。我们还证明，FMRP 的过表达可以部分挽救 TSC2 缺陷的 iPSC 衍生神经元中的过度兴奋。这些数据表明，FMRP 失调代表了 TSC 中异常神经元活动发展的一个重要病理机制，并说明了这两种神经遗传疾病之间的分子会聚。
