PUBLICATION
Transcriptomic and morphologic vascular aberrations underlying FCDIIb etiology
- Authors
- Fang, C., Zhang, X., Yang, L., Sun, L., Lu, Y., Liu, Y., Guo, J., Wang, M., Tan, Y., Zhang, J., Gao, X., Zhu, L., Liu, G., Ren, M., Xiao, J., Zhang, F., Ma, S., Zhao, R., Mei, X., Qi, D.
- ID
- ZDB-PUB-250410-1
- Date
- 2025
- Source
- Nature communications 16: 33203320 (Journal)
- Registered Authors
- Keywords
- none
- MeSH Terms
-
- TOR Serine-Threonine Kinases/metabolism
- Disease Models, Animal
- Animals
- Myocytes, Smooth Muscle/metabolism
- Myocytes, Smooth Muscle/pathology
- Adult
- Drug Resistant Epilepsy*/etiology
- Drug Resistant Epilepsy*/genetics
- Drug Resistant Epilepsy*/pathology
- Transcriptome*
- Male
- Astrocytes/metabolism
- Astrocytes/pathology
- Hypoxia-Inducible Factor 1, alpha Subunit/metabolism
- Neurons/metabolism
- Neurons/pathology
- Vascular Malformations*/genetics
- Vascular Malformations*/pathology
- Brain/blood supply
- Brain/metabolism
- Brain/pathology
- Malformations of Cortical Development, Group I*/etiology
- Malformations of Cortical Development, Group I*/genetics
- Malformations of Cortical Development, Group I*/pathology
- Female
- Zebrafish
- Humans
- PubMed
- 40199880 Full text @ Nat. Commun.
Citation
Fang, C., Zhang, X., Yang, L., Sun, L., Lu, Y., Liu, Y., Guo, J., Wang, M., Tan, Y., Zhang, J., Gao, X., Zhu, L., Liu, G., Ren, M., Xiao, J., Zhang, F., Ma, S., Zhao, R., Mei, X., Qi, D. (2025) Transcriptomic and morphologic vascular aberrations underlying FCDIIb etiology. Nature communications. 16:33203320.
Abstract
Focal cortical dysplasia type II (FCDII) is a major cause of drug-resistant epilepsy, but genetic factors explain only some cases, suggesting other mechanisms. In this study, we conduct a molecular analysis of brain lesions and adjacent areas in FCDIIb patients. By analyzing over 217,506 single-nucleus transcriptional profiles from 15 individuals, we find significant changes in smooth muscle cells (SMCs) and astrocytes. We identify abnormal vascular malformations and a unique type of SMC that we call "Firework cells", which migrate from blood vessels into the brain parenchyma and associate with VIM+ cells. These abnormalities create localized ischemic-hypoxic (I/H) microenvironments, as confirmed by clinical data, further impairing astrocyte function, activating the HIF-1α/mTOR/S6 pathway, and causing neuronal loss. Using zebrafish models, we demonstrate that vascular abnormalities resulting in I/H environments promote seizures. Our results highlight vascular malformations as a factor in FCDIIb pathogenesis, suggesting potential therapeutic avenues.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping