美国耶鲁大学Kaya Bilguvar等研究人员合作发现，mTOR信号通路的失调是平脑症的汇聚机制。相关论文于2025年1月1日在线发表在《自然》杂志上。

研究人员确立了mTOR通路的低活性作为平脑症谱系疾病中的临床相关分子机制。研究人员表征了两种来源于遗传不同的平脑症个体的脑类器官，这些个体分别携带隐性突变p53诱导死亡结构蛋白1（PIDD1）或异合子染色体17p13.3微缺失，导致米勒-迪克尔平脑症综合症（MDLS）。

PIDD1突变脑类器官和MDLS脑类器官再现了人类平脑症的典型增厚皮层，并展示了蛋白质翻译、代谢和mTOR通路的失调。特异性激活mTOR复合物1的脑选择性激活剂能够防止并逆转平脑症类器官中的细胞和分子缺陷。这些发现表明，汇聚的分子机制有助于两种遗传上不同的平脑症谱系疾病的发生。

据了解，人类大脑皮层的发育是一个高度复杂且协调的过程，受到严格的基因调控。罕见的突变改变基因的表达或功能，可能会破坏大脑皮层的结构，导致一系列神经系统疾病。平脑症（“光滑脑”）谱系疾病是一组罕见的、遗传异质性的先天性脑部畸形，通常与癫痫和智力障碍相关。然而，导致这些疾病发生的分子机制仍不明确。

附：英文原文

Title: Dysregulation of mTOR signalling is a converging mechanism in lissencephaly

Author: Zhang, Ce, Liang, Dan, Ercan-Sencicek, A. Gulhan, Bulut, Aybike S., Cortes, Joelly, Cheng, Iris Q., Henegariu, Octavian, Nishimura, Sayoko, Wang, Xinyuan, Peksen, A. Buket, Takeo, Yutaka, Caglar, Caner, Lam, TuKiet T., Koroglu, Merve Nur, Narayanan, Anand, Lopez-Giraldez, Francesc, Miyagishima, Danielle F., Mishra-Gorur, Ketu, Barak, Tanyeri, Yasuno, Katsuhito, Erson-Omay, E. Zeynep, Yalcinkaya, Cengiz, Wang, Guilin, Mane, Shrikant, Kaymakcalan, Hande, Guzel, Aslan, Caglayan, A. Okay, Tuysuz, Beyhan, Sestan, Nenad, Gunel, Murat, Louvi, Angeliki, Bilguvar, Kaya

Issue&Volume: 2025-01-01

Abstract: Cerebral cortex development in humans is a highly complex and orchestrated process that is under tight genetic regulation. Rare mutations that alter gene expression or function can disrupt the structure of the cerebral cortex, resulting in a range of neurological conditions1. Lissencephaly (‘smooth brain’) spectrum disorders comprise a group of rare, genetically heterogeneous congenital brain malformations commonly associated with epilepsy and intellectual disability2. However, the molecular mechanisms underlying disease pathogenesis remain unknown. Here we establish hypoactivity of the mTOR pathway as a clinically relevant molecular mechanism in lissencephaly spectrum disorders. We characterized two types of cerebral organoid derived from individuals with genetically distinct lissencephalies with a recessive mutation in p53-induced death domain protein1 (PIDD1) or a heterozygous chromosome 17p13.3 microdeletion leading to Miller–Dieker lissencephaly syndrome (MDLS). PIDD1-mutant organoids and MDLS organoids recapitulated the thickened cortex typical of human lissencephaly and demonstrated dysregulation of protein translation, metabolism and the mTOR pathway. A brain-selective activator of mTOR complex1 prevented and reversed cellular and molecular defects in the lissencephaly organoids. Our findings show that a converging molecular mechanism contributes to two genetically distinct lissencephaly spectrum disorders.

DOI: 10.1038/s41586-024-08341-9

Source: https://www.nature.com/articles/s41586-024-08341-9