2. Academic Validation
  3. Dysregulation of mTOR signalling is a converging mechanism in lissencephaly

Dysregulation of mTOR signalling is a converging mechanism in lissencephaly

  • Nature. 2025 Feb;638(8049):172-181. doi: 10.1038/s41586-024-08341-9.
Ce Zhang 1 2,  Dan Liang 3 4,  A Gulhan Ercan-Sencicek 5 6,  Aybike S Bulut 5 7,  Joelly Cortes 5,  Iris Q Cheng 5,  Octavian Henegariu 5,  Sayoko Nishimura 5,  Xinyuan Wang 8,  A Buket Peksen 5,  Yutaka Takeo 5,  Caner Caglar 5 9,  TuKiet T Lam 10 11,  Merve Nur Koroglu 12,  Anand Narayanan 13,  Francesc Lopez-Giraldez 13,  Danielle F Miyagishima 2 14,  Ketu Mishra-Gorur 5,  Tanyeri Barak 5 6,  Katsuhito Yasuno 5 6,  E Zeynep Erson-Omay 5 15,  Cengiz Yalcinkaya 16,  Guilin Wang 13 17,  Shrikant Mane 13 14,  Hande Kaymakcalan 5 18,  Aslan Guzel 19 20,  A Okay Caglayan 5 6 21 22,  Beyhan Tuysuz 23,  Nenad Sestan 3 14 24 25 26,  Murat Gunel 27 28 29 30 31 32 33,  Angeliki Louvi 34 35 36,  Kaya Bilguvar 37 38 39 40 41 42 43 44 45
Affiliations

Affiliations

  • 1 Interdepartmental Neuroscience Program, Yale University, New Haven, CT, USA.
  • 2 MD-PhD Program, Yale School of Medicine, New Haven, CT, USA.
  • 3 Department of Neuroscience, Yale School of Medicine, New Haven, CT, USA.
  • 4 Bexorg, Inc., New Haven, CT, USA.
  • 5 Department of Neurosurgery, Yale School of Medicine, New Haven, CT, USA.
  • 6 Yale Program on Neurogenetics, Yale School of Medicine, New Haven, CT, USA.
  • 7 Department of Genome Sciences, Health Sciences Institute, Acibadem University, Istanbul, Turkey.
  • 8 Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
  • 9 Department of Molecular Biology, Beykoz Institute of Life Sciences and Biotechnology, Bezmialem Vakif University, Istanbul, Turkey.
  • 10 Keck MS and Proteomics Resource, Yale School of Medicine, New Haven, CT, USA.
  • 11 Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT, USA.
  • 12 Department of Biostatistics and Bioinformatics, Health Sciences Institute, Acibadem University, Istanbul, Turkey.
  • 13 Yale Center for Genome Analysis, Yale University, New Haven, CT, USA.
  • 14 Department of Genetics, Yale School of Medicine, New Haven, CT, USA.
  • 15 Department of Biomedical Informatics and Data Science, Yale School of Medicine, New Haven, CT, USA.
  • 16 Department of Neurology, Cerrahpasa Medical School, Istanbul University Cerrahpasa, Istanbul, Turkey.
  • 17 Keck Microarray Shared Resource, Yale School of Medicine, New Haven, CT, USA.
  • 18 Department of Translational Medicine, Health Sciences Institute, Acibadem University, Istanbul, Turkey.
  • 19 Department of Neurosurgery, Faculty of Medicine, Bahcesehir University, Istanbul, Turkey.
  • 20 Department of Neurosurgery, Medical Point Hospital, Gaziantep, Turkey.
  • 21 Department of Medical Genetics, Faculty of Medicine, Dokuz Eylul University, Izmir, Turkey.
  • 22 Department of Molecular Medicine, Institute of Health Sciences, Dokuz Eylul University, Izmir, Turkey.
  • 23 Department of Pediatric Genetics, Cerrahpasa Medical School, Istanbul University Cerrahpasa, Istanbul, Turkey.
  • 24 Department of Comparative Medicine, Yale School of Medicine, New Haven, CT, USA.
  • 25 Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA.
  • 26 Kavli Institute for Neuroscience, Yale School of Medicine, New Haven, CT, USA.
  • 27 Department of Neuroscience, Yale School of Medicine, New Haven, CT, USA. murat.gunel@yale.edu.
  • 28 Department of Neurosurgery, Yale School of Medicine, New Haven, CT, USA. murat.gunel@yale.edu.
  • 29 Yale Program on Neurogenetics, Yale School of Medicine, New Haven, CT, USA. murat.gunel@yale.edu.
  • 30 Yale Center for Genome Analysis, Yale University, New Haven, CT, USA. murat.gunel@yale.edu.
  • 31 Department of Genetics, Yale School of Medicine, New Haven, CT, USA. murat.gunel@yale.edu.
  • 32 Yale Program in Brain Tumor Research, Yale School of Medicine, New Haven, CT, USA. murat.gunel@yale.edu.
  • 33 Yale Cancer Center, Yale School of Medicine, New Haven, CT, USA. murat.gunel@yale.edu.
  • 34 Department of Neuroscience, Yale School of Medicine, New Haven, CT, USA. angeliki.louvi@yale.edu.
  • 35 Department of Neurosurgery, Yale School of Medicine, New Haven, CT, USA. angeliki.louvi@yale.edu.
  • 36 Yale Program on Neurogenetics, Yale School of Medicine, New Haven, CT, USA. angeliki.louvi@yale.edu.
  • 37 Department of Neurosurgery, Yale School of Medicine, New Haven, CT, USA. kaya.bilguvar@yale.edu.
  • 38 Yale Program on Neurogenetics, Yale School of Medicine, New Haven, CT, USA. kaya.bilguvar@yale.edu.
  • 39 Department of Genome Sciences, Health Sciences Institute, Acibadem University, Istanbul, Turkey. kaya.bilguvar@yale.edu.
  • 40 Department of Biostatistics and Bioinformatics, Health Sciences Institute, Acibadem University, Istanbul, Turkey. kaya.bilguvar@yale.edu.
  • 41 Yale Center for Genome Analysis, Yale University, New Haven, CT, USA. kaya.bilguvar@yale.edu.
  • 42 Department of Genetics, Yale School of Medicine, New Haven, CT, USA. kaya.bilguvar@yale.edu.
  • 43 Department of Translational Medicine, Health Sciences Institute, Acibadem University, Istanbul, Turkey. kaya.bilguvar@yale.edu.
  • 44 Department of Medical Genetics, School of Medicine, Acibadem University, Istanbul, Turkey. kaya.bilguvar@yale.edu.
  • 45 Rare Diseases and Orphan Drugs Application and Research Center-ACURARE, Acibadem University, Istanbul, Turkey. kaya.bilguvar@yale.edu.
PMID: 39743596 DOI: 10.1038/s41586-024-08341-9
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.

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