Dysregulation of mTOR signalling is a converging mechanism in lissencephaly

Ce Zhang, Dan Liang, A. Gulhan Ercan-Sencicek, Aybike S. Bulut, Joelly Cortes, Iris Q. Cheng, Octavian Henegariu, Sayoko Nishimura, Xinyuan Wang, A. Buket Peksen, Yutaka Takeo, Caner Caglar, TuKiet T. Lam, Merve Nur Koroglu, Anand Narayanan, Francesc Lopez-Giraldez, Danielle F. Miyagishima, Ketu Mishra-Gorur, Tanyeri Barak, Katsuhito Yasuno, E. Zeynep Erson-Omay, Cengiz Yalcinkaya, Guilin Wang, Shrikant Mane, Hande Kaymakcalan, Aslan Guzel, A. Okay Caglayan, Beyhan Tuysuz, Nenad Sestan, Murat Gunel (), Angeliki Louvi () and Kaya Bilguvar ()
Additional contact information
Ce Zhang: Yale University
Dan Liang: Yale School of Medicine
A. Gulhan Ercan-Sencicek: Yale School of Medicine
Aybike S. Bulut: Yale School of Medicine
Joelly Cortes: Yale School of Medicine
Iris Q. Cheng: Yale School of Medicine
Octavian Henegariu: Yale School of Medicine
Sayoko Nishimura: Yale School of Medicine
Xinyuan Wang: Brigham and Women’s Hospital and Harvard Medical School
A. Buket Peksen: Yale School of Medicine
Yutaka Takeo: Yale School of Medicine
Caner Caglar: Yale School of Medicine
TuKiet T. Lam: Yale School of Medicine
Merve Nur Koroglu: Acibadem University
Anand Narayanan: Yale University
Francesc Lopez-Giraldez: Yale University
Danielle F. Miyagishima: Yale School of Medicine
Ketu Mishra-Gorur: Yale School of Medicine
Tanyeri Barak: Yale School of Medicine
Katsuhito Yasuno: Yale School of Medicine
E. Zeynep Erson-Omay: Yale School of Medicine
Cengiz Yalcinkaya: Istanbul University Cerrahpasa
Guilin Wang: Yale University
Shrikant Mane: Yale University
Hande Kaymakcalan: Yale School of Medicine
Aslan Guzel: Bahcesehir University
A. Okay Caglayan: Yale School of Medicine
Beyhan Tuysuz: Istanbul University Cerrahpasa
Nenad Sestan: Yale School of Medicine
Murat Gunel: Yale School of Medicine
Angeliki Louvi: Yale School of Medicine
Kaya Bilguvar: Yale School of Medicine

Nature, 2025, vol. 638, issue 8049, 172-181

Abstract: 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 protein 1 (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 complex 1 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.

Date: 2025
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DOI: 10.1038/s41586-024-08341-9

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