Prions activate a p38 MAPK synaptotoxic signaling pathway.
Prions activate a p38 MAPK synaptotoxic signaling pathway.
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DOI：
10.1371/journal.ppat.1007283
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发表时间：
2018-09
期刊：
影响因子：
6.7
通讯作者：
Harris DA
中科院分区：
文献类型：
--
作者：
Fang C;Wu B;Le NTT;Imberdis T;Mercer RCC;Harris DA
突触变性是朊病毒病最早的病理相关性之一，并且是临床症状进展的主要决定因素。然而，朊病毒突触毒性的细胞和分子机制知之甚少。在此之前，我们描述了一个实验系统，其中处理培养的海马神经元与纯化的PrPSc，感染性形式的朊病毒蛋白，诱导树突棘的快速收缩，这种效果是完全依赖于内源性PrPC的靶神经元的表达。在这里，我们使用这个系统来剖析潜在的细胞和分子机制。我们发现，PrPSc启动一个逐步突触毒性信号级联反应，包括激活NMDA受体，钙离子流入，刺激p38 MAPK和几个下游激酶，和崩溃的肌动蛋白细胞骨架内树突棘。突触变性仅限于兴奋性突触，保留突触前结构，并导致功能性突触传递减少。药理学抑制信号级联中的任何一个步骤，以及显性负性形式的p38 MAPK的表达，阻断PrPSc诱导的脊柱变性。此外，p38 MAPK抑制剂实际上逆转了已经开始的退行性过程。我们还表明，虽然PrPC介导PrPSc和阿尔茨海默氏Aβ肽在该系统中的突触毒性作用，但这两种物质激活不同的信号通路。总之，我们的研究结果为朊病毒神经毒性的生物学提供了强有力的见解，他们确定了新的，可药物治疗的目标，他们允许朊病毒突触毒性通路与其他神经退行性疾病中涉及的通路进行比较。朊病毒病是一组致命的神经退行性疾病，包括人类的克雅氏病和库鲁病，以及牛的牛海绵状脑病。传播这些疾病的感染因子或朊病毒是一种裸露的蛋白质分子，即朊病毒蛋白（PrP），它是正常细胞蛋白的一种变异形式。尽管我们对朊病毒如何自我繁殖和传播感染已经有了很多了解，但它们实际上导致神经元退化的过程仍然是个谜。在这里，我们使用了一个专门的神经元培养系统来剖析朊病毒破坏突触的细胞和分子机制，突触是连接神经细胞的结构，在学习、记忆和神经疾病中起着至关重要的作用。我们的研究结果定义了朊病毒突触毒性的一个逐步的分子途径，包括谷氨酸神经递质受体的激活，钙离子流入神经元，刺激特定的促分裂原活化蛋白激酶，将磷酸基团连接到蛋白质上以调节其活性。我们证明，特定的药物，以及显性负性激酶突变体，阻止这些步骤，从而防止由朊病毒产生的突触变性。我们的研究结果为朊病毒疾病的发病机制提供了新的见解，它们揭示了治疗这些疾病的新药物靶点，并且它们使我们能够将朊病毒疾病与其他更常见的神经退行性疾病（如阿尔茨海默病）进行比较。
Synaptic degeneration is one of the earliest pathological correlates of prion disease, and it is a major determinant of the progression of clinical symptoms. However, the cellular and molecular mechanisms underlying prion synaptotoxicity are poorly understood. Previously, we described an experimental system in which treatment of cultured hippocampal neurons with purified PrPSc, the infectious form of the prion protein, induces rapid retraction of dendritic spines, an effect that is entirely dependent on expression of endogenous PrPC by the target neurons. Here, we use this system to dissect pharmacologically the underlying cellular and molecular mechanisms. We show that PrPSc initiates a stepwise synaptotoxic signaling cascade that includes activation of NMDA receptors, calcium influx, stimulation of p38 MAPK and several downstream kinases, and collapse of the actin cytoskeleton within dendritic spines. Synaptic degeneration is restricted to excitatory synapses, spares presynaptic structures, and results in decrements in functional synaptic transmission. Pharmacological inhibition of any one of the steps in the signaling cascade, as well as expression of a dominant-negative form of p38 MAPK, block PrPSc-induced spine degeneration. Moreover, p38 MAPK inhibitors actually reverse the degenerative process after it has already begun. We also show that, while PrPC mediates the synaptotoxic effects of both PrPSc and the Alzheimer’s Aβ peptide in this system, the two species activate distinct signaling pathways. Taken together, our results provide powerful insights into the biology of prion neurotoxicity, they identify new, druggable therapeutic targets, and they allow comparison of prion synaptotoxic pathways with those involved in other neurodegenerative diseases. Prion diseases are a group of fatal neurodegenerative disorders that includes Creutzfeldt-Jakob disease and kuru in humans, and bovine spongiform encephalopathy in cattle. The infectious agent, or prion, that transmits these diseases is a naked protein molecule, the prion protein (PrP), which is an altered form of a normal, cellular protein. Although a great deal is known about how prions propagate themselves and transmit infection, the process by which they actually cause neurons to degenerate has remained mysterious. Here, we have used a specialized neuronal culture system to dissect the cellular and molecular mechanisms by which prions damage synapses, the structures that connect nerve cells and that play a crucial role in learning, memory, and neurological disease. Our results define a stepwise molecular pathway underlying prion synaptic toxicity, which involves activation of glutamate neurotransmitter receptors, influx of calcium ions into the neuron, and stimulation of specific mitogen-activated protein kinases, which attach phosphate groups to proteins to regulate their activity. We demonstrate that specific drugs, as well as a dominant-negative kinase mutant, block these steps and thereby prevent the synaptic degeneration produced by prions. Our results provide new insights into the pathogenesis of prion diseases, they uncover new drug targets for treating these diseases, and they allow us to compare prion diseases to other, more common neurodegenerative disorders like Alzheimer’s disease.
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影响因子：
2.4
作者：
Borders AS;de Almeida L;Van Eldik LJ;Watterson DM
通讯作者：
Watterson DM
影响因子：
15.9
作者：
Biasini E;Turnbaugh JA;Unterberger U;Harris DA
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Harris DA
DOI：
10.1046/j.1365-2990.2000.026002143.x
发表时间：
2000-04-01
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5
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通讯作者：
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25
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影响因子：
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作者：
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通讯作者：
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