Downregulation of the Repressor Element 1-Silencing Transcription Factor (REST) Is Associated with Akt-mTOR and Wnt-β-Catenin Signaling in Prion Diseases Models.
Downregulation of the Repressor Element 1-Silencing Transcription Factor (REST) Is Associated with Akt-mTOR and Wnt-β-Catenin Signaling in Prion Diseases Models.
复制标题
朊病毒疾病模型中阻遏元件 1-沉默转录因子 (REST) 的下调与 Akt-mTOR 和 Wnt-β-Catenin 信号转导相关
DOI：
10.3389/fnmol.2017.00128
复制
发表时间：
2017
影响因子：
4.8
通讯作者：
Zhao D
中科院分区：
文献类型：
--
作者：
Song Z;Shah SZA;Yang W;Dong H;Yang L;Zhou X;Zhao D
Prion病是一组以多种神经病理改变为特征的感染性疾病，但其保护功能和防止Prion相关神经退变的机制尚不清楚。我们先前报道了抑制因子1沉默转录因子(REST)可以减轻PrP106-126对原代神经元的毒性作用。在这里，我们证实了263K感染仓鼠的体外模型的结果，这是一个体内的普恩病毒疾病的模型，并进一步显示了REST与相关信号通路之间的关系。在普恩病毒感染的大脑中，其余部分从细胞核中被耗尽，并被细胞质中的自噬小体摄取，与LC3-II共同定位。重要的是，Akt-mTor的下调和至少部分失活的LRP6-WNT-β-catenin信号通路与263K感染的仓鼠体内和体外PrP106-126处理的原代神经元中静息水平的降低相关。在原代皮质神经元中过表达REST可减轻PrP106-126肽诱导的神经元氧化应激和线粒体损伤，并部分抑制LRP6-WNT-β-catenin和Akt-mTor信号转导。基于我们的发现，我们提出了一个以Akt-mTOR和Wnt-β-catenin信号通路为关键通路的静息介导的普恩病毒感染动物神经保护模型。REST介导的神经元存活信号可被探索为Pron疾病和相关神经退行性疾病的一个可行的治疗靶点。
Prion diseases are a group of infectious diseases characterized by multiple neuropathological changes, yet the mechanisms that preserve function and protect against prion-associated neurodegeneration are still unclear. We previously reported that the repressor element 1-silencing transcription factor (REST) alleviates neurotoxic prion peptide (PrP106-126)-induced toxicity in primary neurons. Here we confirmed the findings of the in vitro model in 263K infected hamsters, an in vivo model of prion diseases and further showed the relationships between REST and related signaling pathways. REST was depleted from the nucleus in prion infected brains and taken up by autophagosomes in the cytoplasm, co-localizing with LC3-II. Importantly, downregulation of the Akt–mTOR and at least partially inactivation of LRP6-Wnt-β-catenin signaling pathways correlated with the decreased levels of REST in vivo in the brain of 263K-infected hamsters and in vitro in PrP106-126-treated primary neurons. Overexpression of REST in primary cortical neurons alleviated PrP106-126 peptide-induced neuronal oxidative stress, mitochondrial damage and partly inhibition of the LRP6-Wnt-β-catenin and Akt–mTOR signaling. Based on our findings, a model of REST-mediated neuroprotection in prion infected animals is proposed, with Akt–mTOR and Wnt-β-catenin signaling as the key pathways. REST-mediated neuronal survival signaling could be explored as a viable therapeutic target for prion diseases and related neurodegenerative diseases.