Lithium alleviates neurotoxic prion peptide-induced synaptic damage and neuronal death partially by the upregulation of nuclear target REST and the restoration of Wnt signaling
Lithium alleviates neurotoxic prion peptide-induced synaptic damage and neuronal death partially by the upregulation of nuclear target REST and the restoration of Wnt signaling
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锂部分通过上调核靶点 REST 和恢复 Wnt 信号来减轻神经毒性朊病毒肽诱导的突触损伤和神经元死亡
DOI：
10.1016/j.neuropharm.2017.05.021
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发表时间：
2017-09
影响因子：
4.7
通讯作者：
Zhao Deming
中科院分区：
文献类型：
--
作者：
Song Zhiqi;Yang Wei;Zhou Xiangmei;Yang Lifeng;Zhao Deming
朊病毒病是一组以多种神经病理学特征为特征的传染性神经退行性疾病，包括PrPSc的积累、突触损伤和神经元死亡。我们以前报道过，阻遏元件1沉默转录因子（REST），一种新的神经保护性标志物在神经变性，保护神经元免受神经毒性肽（PrP 106 -126）诱导的神经毒性，但未能维持生存后，长期暴露于PrP 106 -126。由于Wnt信号传导部分诱导REST并被锂激活，我们研究了锂对朊病毒疾病中REST的影响。锂恢复REST的核表达，这是调节生存蛋白质所必需的。当REST被阻断时，锂还模拟神经保护功能，并且这些有益作用在生理条件下与REST过表达相加。反过来，在PrP 106 -126刺激的病理条件下，REST在锂治疗的神经保护机制中起关键作用。虽然锂通过抑制糖原合成酶激酶-3 β和稳定β-连环蛋白恢复Wnt信号传导，但在暴露于PrP 106 -126后恢复原代皮层神经元中的存活相关蛋白。REST的敲除显著抑制锂的神经保护功能。相反，REST的过度表达部分恢复了它的作用。值得注意的是，锂通过阻止突触前和突触后标志物蛋白的变化并促进存活途径（也部分通过REST的表达）来直接抑制PrP 106 -126诱导的突触损伤和神经元细胞死亡。我们的研究结果表明，REST作为一个新的和重要的核目标的锂。我们假设PrP 106 -126刺激的神经毒性诱导Wnt信号传导功能障碍，锂模拟这种信号级联反应，这表明锂应被视为一种潜在的治疗剂对朊病毒疾病。
Prion diseases are a group of infectious neurodegenerative diseases characterized by multiple neuropathological hallmarks, including accumulation of PrPSc, synaptic damage, and neuronal death. We previously reported that the repressor element 1-silencing transcription factor (REST), a novel neuroprotective marker in neurodegeneration, protects neurons against neurotoxic peptide (PrP106-126)-induced neurotoxicity, but fails to maintain survival following prolonged exposure to PrP106-126. Because Wnt signaling partially induces REST and is activated by lithium, we investigated the effects of lithium on REST in prion diseases. Lithium restores nuclear expression of REST, which is essential for regulating survival proteins. Lithium also mimics neuroprotective functions when REST is blocked, and these beneficial effects are additive with REST overexpression under physiological conditions. Reciprocally, under PrP106-126-stimulated pathological conditions, REST plays a critical role in the neuroprotective mechanisms of lithium treatment. Although lithium recovers Wnt signaling by inhibiting glycogen synthase kinase-3β and stabilizing β-catenin, restores survival associated proteins after exposure to PrP106-126 in primary cortical neurons. Knockdown of REST significantly suppresses the neuroprotective function of lithium. Conversely, overexpression of REST partially recovers its actions. Notably, lithium directly alleviates PrP106-126-induced synaptic damage and neuronal cell death by preventing changes in presynaptic and postsynaptic marker proteins and promoting survival pathways also partially via the expression of REST. Our results suggest that REST acts as a novel and important nuclear target for lithium. We hypothesize that PrP106-126-stimulated neurotoxicity induces Wnt signaling dysfunction and lithium mimics this signaling cascade, suggesting that lithium should be considered as a potential therapeutic agent against prion diseases.
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影响因子：
5.5
作者：
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影响因子：
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影响因子：
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DOI：
10.1017/s1121189x00000439
发表时间：
2009-09
期刊：
Epidemiologia e Psichiatria Sociale
影响因子：
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L. Tondo;R. Baldessarini
影响因子：
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