Modeling Focal Cortical Dysplasia (FCD) using cortical organoids
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ABSTRACT:
PROVIDER: PRJNA730718 | ENA |
REPOSITORIES: ENA
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Project description:Focal Cortical Dysplasia (FCD) is a frequent cause of drug-resistant focal epilepsy in children and young adults. The international FCD classifications of 2011 and 2022 have identified several clinico-pathological subtypes, either occurring isolated, i.e., FCD ILAE Type 1 or 2, or in association with a principal cortical lesion, i.e., FCD Type 3. Here, we addressed the DNA methylation signature of a previously described new subtype of FCD 3D occurring in the occipital lobe of very young children and microscopically defined by neuronal cell loss in cortical layer 4. We studied the DNA methylation profile using 850K BeadChip arrays in a retrospective cohort of 104 patients with FCD 1A, 2A, 2B, 3D, TLE without FCD, and 16 postmortem specimens without neurological disorders as controls, operated in China or in Germany. DNA was extracted from formalin-fixed paraffin-embedded tissue blocks with microscopically confirmed lesions, and DNA methylation profiles were bioinformatically analyzed with a recently developed deep learning algorithm. Our results revealed a distinct position of FCD 3D in the DNA methylation map of common FCD subtypes, also different from non-FCD epilepsy surgery controls or non-epileptic postmortem controls. Within the FCD 3D cohort, the DNA methylation signature separated three histopathology subtypes, i.e., fibrotic scarring around porencephalic cysts, loss of layer 4, and Rasmussen encephalitis. Differential methylation in FCD 3D with loss of layer 4 specifically mapped to biological pathways related to neurodegeneration, biogenesis of ECM components, axon guidance, and regulation of the actin cytoskeleton. Our data suggest that DNA methylation signatures in cortical malformations are not only of diagnostic value but also phenotypically relevant, providing the molecular underpinnings of structural and histopathological features associated with epilepsy. Further studies will be necessary to confirm these results and clarify their functional relevance and epileptogenic potential in these difficult-to-treat children.
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Project description:Focal Cortical Dysplasia (FCD) is a malformation of the cerebral cortex and a major cause of drug-refractory epilepsy. The role of the diverse brain cell types in FCD development and epileptogenicity is not fully understood. Here, we performed multi-omics single-cell sequencing of cortical lesions and non-lesion areas from individuals with FCD IIa and IIb, the most common presentations of this neurodevelopmental condition. Dissociated nuclei were profiled using the 10X Genomics Multiome ATAC + Gene Expression assay for simultaneous measurement of chromatin accessibility and gene expression in individual nuclei. Integrative analyses of the multimodal cell atlas, which includes 61,525 nuclei with paired open chromatin and gene expression, revealed a loss of upper-layer excitatory neurons and identified a lesion-specific population that expresses the NEFM neurofilament and contains dysmorphic neurons. In glial compartments, we observed a shift towards immature astrocytic populations with the appearance of reactive astrocytes and balloon cells. Additionally, we identified activated microglial cell states emerging in FCD IIb, indicating that neuroinflammation contributes to FCD pathogenesis. This multimodal cell atlas is a valuable resource for exploring the cellular landscape and informing novel therapeutic approaches for cortical malformations.
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