Cell injury and Premature Neurodegeneration in Focal Malformations of Cortical Development

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.

Epilepsy Related to Developmental Tumors and Malformations of Cortical Development

“…Interestingly, tau-positive neuropil threads are observed in cortical regions with prominent immunoreactivity for pS6 and hyperphosphorylated tau is detected in pS6-positive dysmorphic neurons. Moreover, dysmorphic neurons and ballon/giant cells show nuclear and cytoplasmic accumulation of p62 [121], a stress-inducible intracellular protein, which is known to regulate different signal transduction pathways, and has been recently identified as a key target of autophagy (for reviews see [130,131]. A recent study confirms the mTOR-dependent abnormalities in autophagy, indicating a defect in autophagy as a common feature of FCD II and TSC [132].…”

“…Although both FCD II and tubers are characterized by mTOR activation slight differences in the phosphorylation signaling steps have been reported [119]. In contrast, activation of the mTOR pathway has not been reported in FCD type I [117,120,121], supporting the notion that FCD I and FCD II represent two pathogenetically distinct entities.…”

“…Recent observations suggest that abnormal activation of mTOR may contribute to apoptosis signaling pathways and premature activation of mechanisms of neurodegeneration in both FCD II and TSC [121]. Interestingly, tau-positive neuropil threads are observed in cortical regions with prominent immunoreactivity for pS6 and hyperphosphorylated tau is detected in pS6-positive dysmorphic neurons.…”

Immunity and Inflammation in Epilepsy

“…Interestingly, evidence of cell injury and premature neurodegeneration has been reported in TSC, FCD, and GNT (Maldonado et al 2003;Sen et al 2007;Boer et al 2008Boer et al , 2010Choi et al 2009;Iyer et al 2014;Prabowo et al 2014).…”

Os produtos dos genes Tsc1 e Tsc2 em processos neurodegenerativos

“…Anteriormente, o aumento da expressão de alguns fatores da resposta inflamatória havia sido demonstrado em lesões cerebrais (tuberosidades corticais) de pacientes com TSC (BOER et al, 2010), embora esses componentes e a morte celular nessas lesões estejam diretamente relacionados à epilepsia dos pacientes (IYER et al, 2014). Por outro lado, camundongos com nocaute condicional de Tsc1 em células que expressam GFAP não apresentam crises convulsivas mas têm, na quarta semana pós-natal, um aumento da expressão de fatores envolvidos em processo inflamatório no cérebro (ZHANG et al, 2015).…”