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Keywords:

  • apoptosis;
  • cortical tubers;
  • epilepsy;
  • focal cortical dysplasia;
  • mTOR;
  • neurodegeneration

Abstract

Several lines of evidence suggest that cell injury may occur in malformations of cortical development associated with epilepsy. Moreover, recent studies support the link between neurodevelopmental and neurodegenerative mechanisms. We evaluated a series of focal cortical dysplasia (FCD, n = 26; type I and II) and tuberous sclerosis complex (TSC, n = 6) cases. Sections were processed for terminal deoxynucleotidyl transferase-mediated 2′-deoxyuridine 5′-triphosphate nick-end labeling (TUNEL) labeling and immunohistochemistry using markers for the evaluation of apoptosis signaling pathways and neurodegeneration-related proteins/pathways. In both FCD II and TSC specimens, we observed significant increases in both TUNEL-positive and caspase–3-positive cells compared with controls and FCD I. Expression of β-amyloid precursor protein was observed in neuronal soma and processes in FCD II and TSC. In these specimens, we also observed an abnormal expression of death receptor-6. Immunoreactivity for phosphorylated tau was only found in older patients with FCD II and TSC. In these cases, prominent nuclear/cytoplasmic p62 immunoreactivity was detected in both dysmorphic neurons and balloon/giant cells. Our data provide evidence of complex, but similar, mechanisms of cell injury in focal malformations of cortical development associated with mammalian target of rapamycin pathway hyperactivation, with prominent induction of apoptosis-signaling pathways and premature activation of mechanisms of neurodegeneration.