Sodium butyrate causes α-synuclein degradation by an Atg5-dependent and PI3K/Akt/mTOR-related autophagy pathway
Sodium butyrate causes α-synuclein degradation by an Atg5-dependent and PI3K/Akt/mTOR-related autophagy pathway
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丁酸钠通过 Atg5 依赖性和 PI3K/Akt/mTOR 相关的自噬途径导致 α-突触核蛋白降解
DOI：
10.1016/j.yexcr.2019.111772
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发表时间：
2020-02-01
影响因子：
3.7
通讯作者：
Shen, Yan-Qin
中科院分区：
文献类型：
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作者：
Qiao, Chen-Meng;Sun, Meng-Fei;Shen, Yan-Qin
α-突触核蛋白的聚集是帕金森病（PD）发病机制的核心。然而，这些α-突触核蛋白包涵体不仅存在于大脑中，而且存在于肠道中。肠内分泌细胞（EECs）直接暴露于肠腔，可以表达α-突触核蛋白并直接连接到含有α-突触核蛋白的神经。肠道微生物群和微生物代谢产物短链脂肪酸（SCFAs）的生态失调已被认为是PD的驱动因素。丁酸盐是由肠道微生物群产生的SCFA。我们的目的是证明α-突触核蛋白表达在EECs响应丁酸刺激。有趣的是，我们发现丁酸钠（NaB）增加α-突触核蛋白mRNA表达，增强Atg 5介导的自噬（增加LC 3B-II和减少SQSTM 1（也称为p62）表达）在鼠神经内分泌STC-1细胞。此外，通过使用抑制剂巴弗洛霉素A1抑制自噬或通过用siRNA沉默Atg 5来降低α-突触核蛋白mRNA。NaB可显著抑制PI 3 K/Akt/mTOR信号通路，促进细胞凋亡。来自NaB刺激的STC-1细胞的条件培养基在SH-SY 5 Y细胞中诱导炎症。总的来说，NaB通过Atg 5依赖性和PI 3 K/Akt/mTOR相关的自噬途径引起α-Synudein降解。
Aggregation of alpha-Synuclein is central to the pathogenesis of Parkinson's disease (PD). However, these alpha-Synuclein inclusions are not only present in brain, but also in gut. Enteroendocrine cells (EECs), which are directly exposed to the gut lumen, can express alpha-Synuclein and directly connect to alpha-Synuclein-containing nerves. Dysbiosis of gut microbiota and microbial metabolite short-chain fatty acids (SCFAs) has been implicated as a driver for PD. Butyrate is an SCFA produced by the gut microbiota. Our aim was to demonstrate how alpha-Synuclein expression in EECs responds to butyrate stimulation. Interestingly, we found that sodium butyrate (NaB) increases alpha-Synuclein mRNA expression, enhances Atg5-mediated autophagy (increased LC3B-II and decreased SQSTM1 (also known as p62) expression) in murine neuroendocrine STC-1 cells. Further, alpha-Synuclein mRNA was decreased by the inhibition of autophagy by using inhibitor bafilomycin A1 or by silencing Atg5 with siRNA. Moreover, the PI3K/Akt/mTOR pathway was significantly inhibited and cell apoptosis was activated by NaB. Conditioned media from NaB-stimulated STC-1 cells induced inflammation in SH-SY5Y cells. Collectively, NaB causes alpha-Synudein degradation by an Atg5-dependent and PI3K/Akt/mTOR-related autophagy pathway.