PENN Epilepsy Center and Department of Neurology, University of Pennsylvania Medical Center, Philadelphia, Pennsylvania, USA.
J Neuropathol Exp Neurol. 2010 Aug;69(8):850-63. doi: 10.1097/NEN.0b013e3181eac1f5.
Type I and type II focal cortical dysplasias (FCDs) exhibit distinct histopathologic features that suggest different pathogenic mechanisms. Type I FCDs are characterized by mild laminar disorganization and hypertrophic neurons, whereas type II FCDs exhibit dramatic laminar disorganization and cytomegalic cells (balloon cells). Both FCD types are associated with intractable epilepsy; therefore, identifying cellular or molecular differences between these lesion types that explains the histologic differences could provide new diagnostic and therapeutic insights. Type II FCDs express nestin, a neuroglial progenitor protein that is modulated in vitro by the stem cell proteins c-Myc, sex-determining region Y-box 2 (SOX2), and Octamer-4 (Oct-4) after activation of mammalian target of rapamycin complex 1 (mTORC1). Because mTORC1 activation has been demonstrated in type II FCDs, we hypothesized that c-Myc, SOX2, and Oct-4 expression would distinguish type II from type I FCDs. In addition, we assayed the expression of progenitor cell proteins forkhead box G1 (FOXG1), Kruppel-like factor 4 (KLF4), Nanog, and SOX3. Differential expression of 7 stem cellproteins and aberrant phosphorylation of2mTORC1 substrates, S6 andS6 kinase 1 proteins, clearly distinguished type II from type I FCDs(n = 10 each). Our results demonstrate new potential pathogenic pathways in type II FCDs and suggest biomarkers for diagnostic pathology in resected epilepsy specimens.
I 型和 II 型局灶性皮质发育不良（FCD）表现出不同的组织病理学特征，提示不同的发病机制。I 型 FCD 的特征是轻度的层状排列紊乱和肥大神经元，而 II 型 FCD 则表现出明显的层状排列紊乱和巨细胞（气球细胞）。两种 FCD 类型均与难治性癫痫有关；因此，鉴定这些病变类型之间的细胞或分子差异，这些差异可以解释组织学差异，为新的诊断和治疗提供新的思路。II 型 FCD 表达巢蛋白，这是一种神经胶质前体细胞蛋白，在哺乳动物雷帕霉素靶蛋白复合物 1（mTORC1）激活后，可被干细胞蛋白 c-Myc、性别决定区 Y 盒 2（SOX2）和八聚体-4（Oct-4）体外调节。由于 mTORC1 的激活已在 II 型 FCD 中得到证实，我们假设 c-Myc、SOX2 和 Oct-4 的表达将区分 II 型和 I 型 FCD。此外，我们还检测了前体细胞蛋白叉头框 G1（FOXG1）、Kruppel 样因子 4（KLF4）、Nanog 和 SOX3 的表达。7 种干细胞蛋白的差异表达和 2 种 mTORC1 底物 S6 和 S6 激酶 1 蛋白的异常磷酸化，明确区分了 II 型和 I 型 FCD（每组各 10 例）。我们的结果表明，II 型 FCD 中有新的潜在发病途径，并为切除癫痫标本的诊断病理学提供了生物标志物。
