MicroRNA-26a/Death-Associated Protein Kinase 1 Signaling Induces Synucleinopathy and Dopaminergic Neuron Degeneration in Parkinson's Disease.
MicroRNA-26a/Death-Associated Protein Kinase 1 Signaling Induces Synucleinopathy and Dopaminergic Neuron Degeneration in Parkinson's Disease.
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MicroRNA-26a/死亡相关蛋白激酶 1 信号传导诱导帕金森病中的突触核蛋白病和多巴胺能神经元变性
DOI：
10.1016/j.biopsych.2018.12.008
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发表时间：
2019-05-01
影响因子：
10.6
通讯作者：
Zhu LQ
中科院分区：
文献类型：
--
作者：
Su Y;Deng MF;Xiong W;Xie AJ;Guo J;Liang ZH;Hu B;Chen JG;Zhu X;Man HY;Lu Y;Liu D;Tang B;Zhu LQ
死亡相关蛋白激酶1(DAPK1)是一种广泛分布的丝氨酸/苏氨酸(Ser/Thr)激酶，在阿尔茨海默病(AD)和中风等多种神经系统疾病的细胞死亡中起关键作用。然而，人们对DAPK1在帕金森病(PD)发病机制中的作用知之甚少。帕金森病是第二种最常见的神经退行性疾病。用免疫印迹、免疫组织化学方法检测DAPK1的表达变化。用Q-PCR和FISH技术分析miRNAs在帕金森病小鼠和患者中的表达。采用转杆法、空旷法和撑杆法评价其运动能力。免疫荧光、免疫印迹和滤过器捕捉法检测帕金森病小鼠的联核症。我们发现，由于C/EBPα转录因子的缺失而导致miR-26a的减少，DAPK1在转录后上调。帕金森病小鼠DAPK1的过度表达与神经元性突触核病呈正相关。抑制miR-26a或上调DAPK1会导致野生型(Wt)小鼠的突触核病、DA神经元死亡和运动障碍。相反，通过将DAT-CRE小鼠与DAPK1系小鼠杂交，使DA神经元中的DAPK1基因缺失，有效地挽救了慢性MPTP治疗小鼠的异常。我们进一步证明，DAPK1的过表达通过直接磷酸化α-突触核蛋白的Ser129位点来促进PD样表型。相应地，阻止α-突触核蛋白磷酸化的细胞渗透性竞争多肽可以防止mTP小鼠的运动障碍、突触核病和多巴胺能神经元丢失。我们认为miR-26a/DAPK1信号通路在帕金森病分子和细胞病理的形成中起着至关重要的作用。
Death-associated protein kinase 1 (DAPK1) is a widely distributed serine/threonine (Ser/Thr) kinase that is critical for cell death in multiple neurological disorders, including Alzheimer’s disease (AD) and stroke. However, little is known about the role of DAPK1 in the pathogenesis of Parkinson’s disease (PD), the second most common neurodegenerative disorder. We used western blot, immunohistochemistry to evaluate the alteration of DAPK1. Q-PCR and FISH were used to analyze the expression of miRNAs in PD mice and patient. Rotarod, open field and pole tests were used to evaluate the locomotor ability. Immunofluorescence, western blot and filter trap were used to evaluate synucleinopathy in PD mice. we find that DAPK1 is post-transcriptionally upregulated by a reduction in miR-26a caused by a loss of the C/EBPα transcription factor. The overexpression of DAPK1 in PD mice is positively correlated with neuronal synucleinopathy. Suppressing miR-26a or up-regulating DAPK1 results in synucleinopathy, DA neuron cell death and motor disabilities in wild-type (wt) mice. In contrast, genetic deletion of DAPK1 in DA neurons by crossing the DAT-Cre mice with DAPK1 floxed mice effectively rescues the abnormalities in mice with chronic MPTP treatment. We further show that DAPK1 overexpression promotes PD-like phenotypes by direct phosphorylation of α-synuclein at Ser129 site. Correspondingly, a cell-permeable competing peptide that blocks the phosphorylation of α-synuclein prevents motor disorders, synucleiopathy and dopaminergic neuron loss in the MPTP mice. We conclude that miR-26a/DAPK1 signaling cascades are essential in the formation of the molecular and cellular pathologies in PD.
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中风中通过 DAPK1 和 Tau 造成脊柱损伤的新机制
DOI：
10.1093/cercor/bhv096
发表时间：
2015-11
期刊：
Cerebral cortex (New York, N.Y. : 1991)
影响因子：
--
作者：
Pei L;Wang S;Jin H;Bi L;Wei N;Yan H;Yang X;Yao C;Xu M;Shu S;Guo Y;Yan H;Wu J;Li H;Pang P;Tian T;Tian Q;Zhu LQ;Shang Y;Lu Y
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Lu Y
影响因子：
29.4
作者：
Oakley, Fiona;Teoh, Victoria;Mann, Derek A.
通讯作者：
Mann, Derek A.
影响因子：
11
作者：
HUGHES, AJ;DANIEL, SE;LEES, AJ
通讯作者：
LEES, AJ
影响因子：
4.8
作者：
Mohamed, Junaith S.;Lopez, Michael A.;Boriek, Aladin M.
通讯作者：
Boriek, Aladin M.
影响因子：
4.8
作者：
Doxakis, Epaminondas
通讯作者：
Doxakis, Epaminondas