DLP1-dependent mitochondrial fragmentation and redistribution mediate prion-associated mitochondrial dysfunction and neuronal death.
DLP1-dependent mitochondrial fragmentation and redistribution mediate prion-associated mitochondrial dysfunction and neuronal death.
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DLP1依赖性线粒体断裂和重新分布介导朊病毒相关线粒体功能障碍和神经元死亡
DOI：
10.1111/acel.12693
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发表时间：
2018-03
期刊：
影响因子：
7.8
通讯作者：
Yang L
中科院分区：
文献类型：
--
作者：
Li C;Wang D;Wu W;Yang W;Ali Shah SZ;Zhao Y;Duan Y;Wang L;Zhou X;Zhao D;Yang L
线粒体功能障碍是包括朊病毒病在内的许多神经退行性疾病发病机制中的普遍和关键步骤。发动蛋白样蛋白1（Dynamin‐like protein 1，DLP 1）是线粒体分裂的关键调节因子之一。在这项研究中，我们研究了DLP 1在体外和体内朊病毒疾病模型的神经元线粒体断裂和功能障碍中的作用。线粒体变得碎片化，并从轴突重新分布到索马，与体外用朊病毒肽PrP 106 -126处理的鼠原代神经元（N2 a细胞）以及体内朊病毒株感染的仓鼠脑中线粒体DLP 1表达增加相关。通过DPL 1 RNAi抑制DLP 1表达可抑制朊病毒诱导的线粒体碎片化和功能障碍（通过ADP/ATP比值、线粒体膜电位和线粒体完整性测量）。我们还证明了DLP 1 RNAi对N2 a细胞中的朊病毒肽具有神经保护作用，如通过改善的细胞活力和降低的凋亡标志物（由PrP 106 -126诱导的半胱天冬酶3）所示。相反，DLP 1的过表达加剧了线粒体功能障碍和细胞死亡。此外，DLP 1表达的抑制改善了PrP 106 -126诱导的神经突丢失和突触异常（即，树突棘和PSD-95的损失，突触后支架蛋白作为突触可塑性的标志物），表明改变的DLP 1表达和线粒体片段化是介导PrP 106 -126诱导的神经元损失和变性的上游事件。我们的研究结果表明，DLP 1依赖的线粒体片段化和再分布在PrPS c相关的线粒体功能障碍和神经元凋亡中起着关键作用。抑制DLP 1可能是一种新的有效的预防和治疗朊病毒疾病的策略。
Mitochondrial malfunction is a universal and critical step in the pathogenesis of many neurodegenerative diseases including prion diseases. Dynamin‐like protein 1 (DLP1) is one of the key regulators of mitochondrial fission. In this study, we investigated the role of DLP1 in mitochondrial fragmentation and dysfunction in neurons using in vitro and in vivo prion disease models. Mitochondria became fragmented and redistributed from axons to soma, correlated with increased mitochondrial DLP1 expression in murine primary neurons (N2a cells) treated with the prion peptide PrP106–126 in vitro as well as in prion strain‐infected hamster brain in vivo. Suppression of DLP1 expression by DPL1 RNAi inhibited prion‐induced mitochondrial fragmentation and dysfunction (measured by ADP/ATP ratio, mitochondrial membrane potential, and mitochondrial integrity). We also demonstrated that DLP1 RNAi is neuroprotective against prion peptide in N2a cells as shown by improved cell viability and decreased apoptosis markers, caspase 3 induced by PrP106–126. On the contrary, overexpression of DLP1 exacerbated mitochondrial dysfunction and cell death. Moreover, inhibition of DLP1 expression ameliorated PrP106–126‐induced neurite loss and synaptic abnormalities (i.e., loss of dendritic spine and PSD‐95, a postsynaptic scaffolding protein as a marker of synaptic plasticity) in primary neurons, suggesting that altered DLP1 expression and mitochondrial fragmentation are upstream events that mediate PrP106–126‐induced neuron loss and degeneration. Our findings suggest that DLP1‐dependent mitochondrial fragmentation and redistribution plays a pivotal role in PrPS c‐associated mitochondria dysfunction and neuron apoptosis. Inhibition of DLP1 may be a novel and effective strategy in the prevention and treatment of prion diseases.
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影响因子：
--
作者：
Liu C;Yue R;Yang Y;Cui Y;Yang L;Zhao D;Zhou X
通讯作者：
Zhou X
DOI：
10.1046/j.1365-2990.2000.026002143.x
发表时间：
2000-04-01
影响因子：
5
作者：
Belichenko, PV;Brown, D;Fraser, JR
通讯作者：
Fraser, JR
影响因子：
4.8
作者：
Gu, YP;Fujioka, H;Singh, N
通讯作者：
Singh, N
由状态癫痫诱导的区域特异性星形死亡中的差异DRP1磷酸化和线粒体动力学。
影响因子：
5.3
作者：
Ko AR;Hyun HW;Min SJ;Kim JE
通讯作者：
Kim JE
影响因子：
3.7
作者：
Campeau JL;Wu G;Bell JR;Rasmussen J;Sim VL
通讯作者：
Sim VL