雷帕霉素靶蛋白下调挽救结节性硬化症小鼠模型中的神经元表型。

Raptor downregulation rescues neuronal phenotypes in mouse models of Tuberous Sclerosis Complex.

机构信息

Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, 94720, USA.

Helen Wills Neuroscience Institute, University of California, Berkeley, Berkeley, CA, 94720, USA.

出版信息

Nat Commun. 2022 Aug 9;13(1):4665. doi: 10.1038/s41467-022-31961-6.

Tuberous Sclerosis Complex (TSC) is a neurodevelopmental disorder caused by mutations in the TSC1 or TSC2 genes, which encode proteins that negatively regulate mTOR complex 1 (mTORC1) signaling. Current treatment strategies focus on mTOR inhibition with rapamycin and its derivatives. While effective at improving some aspects of TSC, chronic rapamycin inhibits both mTORC1 and mTORC2 and is associated with systemic side-effects. It is currently unknown which mTOR complex is most relevant for TSC-related brain phenotypes. Here we used genetic strategies to selectively reduce neuronal mTORC1 or mTORC2 activity in mouse models of TSC. We find that reduction of the mTORC1 component Raptor, but not the mTORC2 component Rictor, rebalanced mTOR signaling in Tsc1 knock-out neurons. Raptor reduction was sufficient to improve several TSC-related phenotypes including neuronal hypertrophy, macrocephaly, impaired myelination, network hyperactivity, and premature mortality. Raptor downregulation represents a promising potential therapeutic intervention for the neurological manifestations of TSC.

结节性硬化症（TSC）是一种神经发育障碍，由 TSC1 或 TSC2 基因突变引起，这些基因编码的蛋白质负调控 mTOR 复合物 1（mTORC1）信号。目前的治疗策略侧重于使用雷帕霉素及其衍生物抑制 mTOR。虽然雷帕霉素在改善 TSC 的某些方面有效，但慢性雷帕霉素抑制 mTORC1 和 mTORC2，并与全身副作用相关。目前尚不清楚哪种 mTOR 复合物与 TSC 相关的脑表型最相关。在这里，我们使用遗传策略在 TSC 的小鼠模型中选择性地降低神经元 mTORC1 或 mTORC2 的活性。我们发现，降低 mTORC1 成分 Raptor，但不是 mTORC2 成分 Rictor，可使 Tsc1 敲除神经元中的 mTOR 信号重新平衡。Raptor 的减少足以改善几种 TSC 相关表型，包括神经元肥大、大头畸形、髓鞘形成受损、网络过度活跃和过早死亡。下调 Raptor 代表了一种有前途的治疗 TSC 神经表现的潜在治疗干预措施。