Aurea Mediocritas: mTOR Abides the Golden Mean

Dysregulation of mTOR signalling is a converging mechanism in lissencephaly Zhang C, Liang D, Ercan-Sencicek AG, Bulut AS, Cortes J, Cheng IQ, Henegariu O, Nishimura S, Wang X, Peksen AB, Takeo Y, Caglar C, Lam TT, Koroglu MN, Narayanan A, Lopez-Giraldez F, Miyagishima DF, Mishra-Gorur K, Barak T, Yasuno K, Erson-Omay EZ, Yalcinkaya C, Wang G, Mane S, Kaymakcalan H, Guzel A, Caglayan AO, Tuysuz B, Sestan N, Gunel M, Louvi A, Bilguvar K (2025). Nature. 2025;638(8049):172-181. doi: 10.1038/s41586-024-08341-9. PMID: 39743596 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. Lissencephaly ('smooth brain”) spectrum disorders comprise a group of rare, genetically heterogeneous congenital brain malformations commonly associated with epilepsy and intellectual disability. 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 2 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 2 genetically distinct lissencephaly spectrum disorders.