HDAC6 alleviates prion peptide-mediated neuronal death via modulating PI3K-Akt-mTOR pathway
HDAC6 alleviates prion peptide-mediated neuronal death via modulating PI3K-Akt-mTOR pathway
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HDAC6 通过调节 PI3K-Akt-mTOR 通路减轻朊病毒肽介导的神经元死亡
DOI：
10.1016/j.neurobiolaging.2015.09.021
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发表时间：
2016-01
影响因子：
4.2
通讯作者：
Yang, Lifeng
中科院分区：
文献类型：
--
作者：
Zhou, Xiangmei;Yin, Xiaomin;Hassan, Muhammad Farooque;Yang, Lifeng
组蛋白去乙酰化酶6 （HDAC6）控制几种主要的细胞应激反应，这些应激反应在神经退行性疾病中发挥作用，包括聚集体形成、自噬和细胞凋亡。然而，HDAC6在朊病毒疾病中的具体作用尚不清楚。在这项研究中，我们研究了HDAC6与细胞对神经毒性合成朊病毒蛋白片段PrP106-126的反应之间的关系。我们确定大脑皮质神经元暴露于该片段会改变HDAC6的表达和定位。抑制HDAC6活性或敲低HDAC6表达会加重PrP106-126诱导的神经元细胞死亡，而过表达HDAC6可减轻PrP106-126诱导的神经元死亡。我们还发现HDAC6的这种保护作用涉及自噬的激活和pi3k - akt -哺乳动物雷帕霉素靶（mTOR）信号的调节。在PrP106-126刺激下，HDAC6在神经元诱导的自噬中过表达与磷酸化mTOR和磷酸化p70S6K的减少相关，相反，HDAC6缺乏干扰自噬并增加磷酸化mTOR和磷酸化70S6K。此外，HDAC6似乎也调节Akt的磷酸化；过表达HDAC6会增加磷酸化的Akt，但缺乏HDAC6会导致磷酸化的Akt进一步降低。总之，我们证明了HDAC6保护神经元免受朊病毒肽的毒性，并且这种保护是通过调节PI3k-Akt-mTOR轴发生的。
Histone deacetylase 6 (HDAC6) controls several major cellular responses to stress that play a role in neurodegenerative diseases, including aggresome formation, autophagy, and apoptosis. However, the specific role of HDAC6 in prion diseases is not known. In this study, we examined the relationship between HDAC6 and cellular response to the neurotoxic synthetic prion protein fragment PrP106-126. We determined that exposure of cerebral cortical neurons to this fragment alters the expression and localization of HDAC6. Suppression of HDAC6 activity or knockdown of HDAC6 expression exacerbates the neuronal cell death induced by PrP106-126, but that overexpression of HDAC6 alleviates PrP106-126-induced neuronal death. We also found that this protective effect of HDAC6 involves the activation of autophagy and modulation of PI3K-Akt-mammalian target of rapamycin (mTOR) signaling. Overexpression of HDAC6 in neurons-induced autophagy correlated with a reduction in phosphorylated mTOR and phosphorylated p70S6K in response to PrP106-126 stimulation, conversely, HDAC6 deficiency interfered with autophagy and increased phosphorylated mTOR and phosphorylated 70S6K. In addition, HDAC6 also appears to modulate the phosphorylation of Akt; overexpression of HDAC6 increased the phosphorylated Akt, but HDAC6 deficiency resulted in further reduction of phosphorylated Akt. Overall, we demonstrate that HDAC6 protects neurons from toxicity of prion peptide, and that this protection occurs at through the regulation of the PI3k-Akt-mTOR axis.
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影响因子：
4.3
作者：
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通讯作者：
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影响因子：
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作者：
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作者：
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BAT3 的过表达可减轻朊病毒蛋白片段 PrP106-126 诱导的神经元凋亡
影响因子：
5.5
作者：
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通讯作者：
Zhao, De-Ming
DOI：
10.1016/j.bbadis.2008.10.002
发表时间：
2008-12
影响因子：
6.2
作者：
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通讯作者：
Taylor, J. Paul