mTOR's Role in Lissencephaly: A Key Pathway in Cortical Development and Potential Therapies
Lissencephaly is a set of rare structural brain malformations including agyria, pachygyria and subcortical band heterotopia. It is characterized by smooth brain appearance due to absence of cerebral gyri and thickening of the cortical grey matter. Rare mutations are known to be causative effects of disease progression; however, the molecular mechanism of disease pathogenesis is not completely explained. This study utilizes transcriptomic, proteomic, and pharmacological methods on patient-derived organoids to identify dysregulated mTOR signaling as a shared molecular mechanism underlying two genetically distinct lissencephaly spectrum disorders.
The mTOR pathway plays a critical role in human cortical development. Bot mosaic and germline mutations in genes regulating mTOR, which lead to pathway hyperactivation, have been linked to conditions called “mTORopathies” such as hemimegalencephaly, polymicrogyria, focal cortical dysplasia, and tuberous sclerosis. Organoids with hyperactive mTOR signaling commonly exhibit increased neural progenitor proliferation, expansion of outer radial glia (oRG), and delayed neuronal differentiation. This is likely to promote the growth of progenitor cells at the expense of neurogenesis. In contrast, organoids with PIDD1 mutations and those modeling MDLS (Miller-Dieker Lissencephaly Syndrome) with hypoactive mTOR signaling showed increased neurogenesis and an expansion of the cortical plate (CP). These results suggest that PIDD1’s normal role in the cerebral cortex is to sustain progenitor or non-neuronal states through proper mTOR signaling. One proposed mechanism involves mTORC1’s regulation of neuronal differentiation via translational control. Supporting this, the study observed transcriptional dysregulation of translation, impaired ribosome biogenesis, and reduced protein synthesis in lissencephaly organoids. A mechanical simulation model of cortical folding suggested that increased CP thickness could lead to pachygyria or agyria, indicating that restoring normal mTORC1 activity might represent reduced cortical folding seen in lissencephaly spectrum disorders.
In summary, the study reveals that mTOR pathway hypoactivation serves as a shared molecular mechanism in two genetically distinct lissencephaly spectrum disorders, broadening the scope of "mTORopathies," which were previously associated primarily with pathway hyperactivation. These findings highlight a critical molecular pathway for potential therapeutic development in lissencephaly disorders with varying genetic causes. The research further proposes that the mTOR pathway could act as a central hub in cortical misfolding disorders, with disruptions in different genes affecting mTOR signaling and leading to diverse phenotypes, such as lissencephaly or polymicrogyria. This underscores the mTOR pathway’s potential as a convergent therapeutic target.
References:
Zhang, C., Liang, D., Ercan-Sencicek, A.G. et al. Dysregulation of mTOR signalling is a converging mechanism in lissencephaly. Nature (2025). https://doi.org/10.1038/s41586-024-08341-9
