Dysregulation of mTOR signalling is a converging mechanism in lissencephaly.

Autor: Zhang C; Interdepartmental Neuroscience Program, Yale University, New Haven, CT, USA.; MD-PhD Program, Yale School of Medicine, New Haven, CT, USA., Liang D; Department of Neuroscience, Yale School of Medicine, New Haven, CT, USA.; Bexorg, Inc., New Haven, CT, USA., Ercan-Sencicek AG; Department of Neurosurgery, Yale School of Medicine, New Haven, CT, USA.; Yale Program on Neurogenetics, Yale School of Medicine, New Haven, CT, USA., Bulut AS; Department of Neurosurgery, Yale School of Medicine, New Haven, CT, USA.; Department of Genome Sciences, Health Sciences Institute, Acibadem University, Istanbul, Turkey., Cortes J; Department of Neurosurgery, Yale School of Medicine, New Haven, CT, USA., Cheng IQ; Department of Neurosurgery, Yale School of Medicine, New Haven, CT, USA., Henegariu O; Department of Neurosurgery, Yale School of Medicine, New Haven, CT, USA., Nishimura S; Department of Neurosurgery, Yale School of Medicine, New Haven, CT, USA., Wang X; Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA., Peksen AB; Department of Neurosurgery, Yale School of Medicine, New Haven, CT, USA., Takeo Y; Department of Neurosurgery, Yale School of Medicine, New Haven, CT, USA., Caglar C; Department of Neurosurgery, Yale School of Medicine, New Haven, CT, USA.; Department of Molecular Biology, Beykoz Institute of Life Sciences and Biotechnology, Bezmialem Vakif University, Istanbul, Turkey., Lam TT; Keck MS and Proteomics Resource, Yale School of Medicine, New Haven, CT, USA.; Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT, USA., Koroglu MN; Department of Biostatistics and Bioinformatics, Health Sciences Institute, Acibadem University, Istanbul, Turkey., Narayanan A; Yale Center for Genome Analysis, Yale University, New Haven, CT, USA., Lopez-Giraldez F; Yale Center for Genome Analysis, Yale University, New Haven, CT, USA., Miyagishima DF; MD-PhD Program, Yale School of Medicine, New Haven, CT, USA.; Department of Genetics, Yale School of Medicine, New Haven, CT, USA., Mishra-Gorur K; Department of Neurosurgery, Yale School of Medicine, New Haven, CT, USA., Barak T; Department of Neurosurgery, Yale School of Medicine, New Haven, CT, USA.; Yale Program on Neurogenetics, Yale School of Medicine, New Haven, CT, USA., Yasuno K; Department of Neurosurgery, Yale School of Medicine, New Haven, CT, USA.; Yale Program on Neurogenetics, Yale School of Medicine, New Haven, CT, USA., Erson-Omay EZ; Department of Neurosurgery, Yale School of Medicine, New Haven, CT, USA.; Department of Biomedical Informatics and Data Science, Yale School of Medicine, New Haven, CT, USA., Yalcinkaya C; Department of Neurology, Cerrahpasa Medical School, Istanbul University Cerrahpasa, Istanbul, Turkey., Wang G; Yale Center for Genome Analysis, Yale University, New Haven, CT, USA.; Keck Microarray Shared Resource, Yale School of Medicine, New Haven, CT, USA., Mane S; Yale Center for Genome Analysis, Yale University, New Haven, CT, USA.; Department of Genetics, Yale School of Medicine, New Haven, CT, USA., Kaymakcalan H; Department of Neurosurgery, Yale School of Medicine, New Haven, CT, USA.; Department of Translational Medicine, Health Sciences Institute, Acibadem University, Istanbul, Turkey., Guzel A; Department of Neurosurgery, Faculty of Medicine, Bahcesehir University, Istanbul, Turkey.; Department of Neurosurgery, Medical Point Hospital, Gaziantep, Turkey., Caglayan AO; Department of Neurosurgery, Yale School of Medicine, New Haven, CT, USA.; Yale Program on Neurogenetics, Yale School of Medicine, New Haven, CT, USA.; Department of Medical Genetics, Faculty of Medicine, Dokuz Eylul University, Izmir, Turkey.; Department of Molecular Medicine, Institute of Health Sciences, Dokuz Eylul University, Izmir, Turkey., Tuysuz B; Department of Pediatric Genetics, Cerrahpasa Medical School, Istanbul University Cerrahpasa, Istanbul, Turkey., Sestan N; Department of Neuroscience, Yale School of Medicine, New Haven, CT, USA.; Department of Genetics, Yale School of Medicine, New Haven, CT, USA.; Department of Comparative Medicine, Yale School of Medicine, New Haven, CT, USA.; Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA.; Kavli Institute for Neuroscience, Yale School of Medicine, New Haven, CT, USA., Gunel M; Department of Neuroscience, Yale School of Medicine, New Haven, CT, USA. murat.gunel@yale.edu.; Department of Neurosurgery, Yale School of Medicine, New Haven, CT, USA. murat.gunel@yale.edu.; Yale Program on Neurogenetics, Yale School of Medicine, New Haven, CT, USA. murat.gunel@yale.edu.; Yale Center for Genome Analysis, Yale University, New Haven, CT, USA. murat.gunel@yale.edu.; Department of Genetics, Yale School of Medicine, New Haven, CT, USA. murat.gunel@yale.edu.; Yale Program in Brain Tumor Research, Yale School of Medicine, New Haven, CT, USA. murat.gunel@yale.edu.; Yale Cancer Center, Yale School of Medicine, New Haven, CT, USA. murat.gunel@yale.edu., Louvi A; Department of Neuroscience, Yale School of Medicine, New Haven, CT, USA. angeliki.louvi@yale.edu.; Department of Neurosurgery, Yale School of Medicine, New Haven, CT, USA. angeliki.louvi@yale.edu.; Yale Program on Neurogenetics, Yale School of Medicine, New Haven, CT, USA. angeliki.louvi@yale.edu., Bilguvar K; Department of Neurosurgery, Yale School of Medicine, New Haven, CT, USA. kaya.bilguvar@yale.edu.; Yale Program on Neurogenetics, Yale School of Medicine, New Haven, CT, USA. kaya.bilguvar@yale.edu.; Department of Genome Sciences, Health Sciences Institute, Acibadem University, Istanbul, Turkey. kaya.bilguvar@yale.edu.; Department of Biostatistics and Bioinformatics, Health Sciences Institute, Acibadem University, Istanbul, Turkey. kaya.bilguvar@yale.edu.; Yale Center for Genome Analysis, Yale University, New Haven, CT, USA. kaya.bilguvar@yale.edu.; Department of Genetics, Yale School of Medicine, New Haven, CT, USA. kaya.bilguvar@yale.edu.; Department of Translational Medicine, Health Sciences Institute, Acibadem University, Istanbul, Turkey. kaya.bilguvar@yale.edu.; Department of Medical Genetics, School of Medicine, Acibadem University, Istanbul, Turkey. kaya.bilguvar@yale.edu.; Rare Diseases and Orphan Drugs Application and Research Center-ACURARE, Acibadem University, Istanbul, Turkey. kaya.bilguvar@yale.edu.
Jazyk: angličtina
Zdroj: Nature [Nature] 2025 Jan 01. Date of Electronic Publication: 2025 Jan 01.
DOI: 10.1038/s41586-024-08341-9
Abstrakt: 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 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.
Competing Interests: Competing interests: N.S. is a co-founder and shareholder of Bexorg, Inc. All the other authors declare no competing interests.
(© 2025. The Author(s).)
Databáze: MEDLINE
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