STRADα deficiency results in aberrant mTORC1 signaling during corticogenesis in humans and mice
STRADα deficiency results in aberrant mTORC1 signaling during corticogenesis in humans and mice
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DOI：
10.1172/jci41592
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发表时间：
2010-05-01
影响因子：
15.9
通讯作者：
Crino, Peter B.
中科院分区：
文献类型：
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作者：
Orlova, Ksenia A.;Parker, Whitney E.;Crino, Peter B.
羊水过多、巨脑畸形和症状性癫痫综合征 (PMSE) 是一种罕见的人类常染色体隐性疾病，其特征是大脑发育异常、认知障碍和顽固性癫痫。它是由 STE20 相关激酶接头 α (STRADA) 纯合缺失引起的。 PMSE 的潜在致病机制和 STRADA 在皮质发育中的作用仍不清楚。在这里，我们发现人类 PMSE 大脑表现出细胞肿大、神经元异位和哺乳动物雷帕霉素靶复合物 1 (mTORC1) 信号传导的异常激活。 STRAD α 通常结合蛋白激酶 LKB1 并将其输出到细胞核外，从而抑制 mTORC1 通路。我们发现人类 PMSE 皮层的神经元表现出 LKB1 的异常核定位。为了进一步研究这一点，我们在体外模拟了小鼠神经祖细胞 (mNPC) 的 PMSE 模型，并通过敲低 STRAD α 的表达来模拟了体内发育中的小鼠皮质的 PMSE。 STRAD α 缺陷的 mNPC 细胞肿大，并表现出与 LKB1 核定位异常相关的 mTORC1 异常雷帕霉素依赖性激活。与人类 PMSE 大脑中的观察结果一致，体内 STRAD α 的敲低导致皮质畸形、mTORC1 激活增强以及 LKB1 核定位异常。因此，我们认为由 STRAD α 缺陷引起的 LKB1 异常核积累有助于 mTORC1 信号传导的过度激活和皮质发生过程中神经元层压的破坏，从而导致与 PMSE 相关的神经学特征。
Polyhydramnios, megalencephaly, and symptomatic epilepsy syndrome (PMSE) is a rare human autosomal-recessive disorder characterized by abnormal brain development, cognitive disability, and intractable epilepsy. It is caused by homozygous deletions of STE20-related kinase adaptor alpha (STRADA). The underlying pathogenic mechanisms of PMSE and the role of STRADA in cortical development remain unknown. Here, we found that a human PMSE brain exhibits cytomegaly, neuronal heterotopia, and aberrant activation of mammalian target of rapamycin complex 1 (mTORC1) signaling. STRAD alpha normally binds and exports the protein kinase LKB1 out of the nucleus, leading to suppression of the mTORC1 pathway. We found that neurons in human PMSE cortex exhibited abnormal nuclear localization of LKB1. To investigate this further, we modeled PMSE in mouse neural progenitor cells (mNPCs) in vitro and in developing mouse cortex in vivo by knocking down STRAD alpha expression. STRAD alpha-deficient mNPCs were cytomegalic and showed aberrant rapamycin-dependent activation of mTORC1 in association with abnormal nuclear localization of LKB1. Consistent with the observations in human PMSE brain, knockdown of STRAD alpha in vivo resulted in cortical malformation, enhanced mTORC1 activation, and abnormal nuclear localization of LKB1. Thus, we suggest that the aberrant nuclear accumulation of LKB1 caused by STRAD alpha deficiency contributes to hyperactivation of mTORC1 signaling and disruption of neuronal lamination during corticogenesis, and thereby the neurological features associated with PMSE.