Dysregulation of mTOR signalling is a converging mechanism in lissencephaly

• 成果类型: Article
• 署名作者: 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
• 署名单位: Yale University; Yale University; Yale University; Yale University; Yale University; Acibadem University; Harvard University; Harvard University Medical Affiliates; Brigham & Women's Hospital; Harvard University; Harvard Medical School; Yale University; Yale University; Acibadem University; Yale University; Yale University; Yale University; Istanbul University - Cerrahpasa; Yale University; Acibadem University; Bahcesehir University; Dokuz Eylul University; Dokuz Eylul University; Istanbul University - Cerrahpasa; Yale University; Yale University; Yale University; Yale University; Yale University; Yale New Haven Hospital; Acibadem University; Acibadem University; Bezmialem Vakif University
• 刊物名称: Nature
• ISSN/ISSBN: 0028-1188
• DOI: 10.1038/s41586-024-08341-9
• 发表日期: 2025-02-01
• 页码: 172-+
• 关键词: mental-retardation; MODEL; pachygyria; mutations; apoptosis; target; cradd

摘要

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 conditions(1). Lissencephaly ('smooth brain') spectrum disorders comprise a group of rare, genetically heterogeneous congenital brain malformations commonly associated with epilepsy and intellectual disability(2). 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.