Alteration of autophagy-related proteins in peripheral blood mononuclear cells of patients with Parkinson's disease
Alteration of autophagy-related proteins in peripheral blood mononuclear cells of patients with Parkinson's disease
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DOI：
10.1016/j.neurobiolaging.2017.11.006
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发表时间：
2018-03-01
影响因子：
4.2
通讯作者：
Tomiyama, Masahiko
中科院分区：
文献类型：
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作者：
Miki, Yasuo;Shimoyama, Shuji;Tomiyama, Masahiko
先前的尸检研究表明帕金森氏病(PD)患者自噬功能失调。为了阐明这种改变是否反映了帕金森病的一个基本方面，还是代表了由长期神经退变过程引起的自噬失调的最后阶段，我们重点研究了帕金森病患者(n=35)和对照组(n=23)外周血单个核细胞(PBMC)的基础自噬。全转录组分析显示，6个自噬核心调控因子(UNC-51样激酶[ULK]3、自噬相关[ATG]2A、Atg4B、ATG5、Atg16L1和组蛋白脱乙酰酶6)的mRNAs表达下调。逆转录-聚合酶链式反应和Western印迹分析证实，PD患者上游自噬蛋白(ULK1、Beclin1和自噬/Beclin1调节因子1)的蛋白水平显著升高，并且这些蛋白的mRNA表达呈负反馈。这些蛋白水平与外周血单核细胞中α-突触核蛋白水平的升高有关。α-突触核蛋白寡聚体在PBMC中的表达水平与帕金森病的临床严重程度和心脏交感神经变性程度平行。帕金森病患者自噬的基础活性可能较低。基础自噬的改变可能是帕金森病的一个基本方面。(C)2017 Elsevier Inc.保留所有权利。
Previous postmortem studies demonstrated dysregulation of autophagy in patients with Parkinson's disease (PD). To clarify whether this alteration reflects a fundamental aspect of PD or represents the final stage of autophagy dysregulation resulting from a long neurodegenerative process, we focused on basal autophagy in peripheral blood mononuclear cells (PBMCs) of PD patients (n = 35) and controls (n = 23). The whole-transcriptome assay revealed downregulation of mRNAs for 6 core regulators of autophagy (UNC-51-like kinase [ULK] 3, autophagy-related [Atg] 2A, Atg4B, Atg5, Atg16L1, and histone deacetylase 6). Reverse transcriptionepolymerase chain reaction and Western blot analysis confirmed significantly increased protein levels of upstream autophagy (ULK1, Beclin1, and autophagy/beclin1 regulator 1) with negative feedback of mRNA expression for these proteins in PD. These protein levels were correlated with increased levels of alpha-synuclein in PBMCs. The expression level of the oligomeric form of alpha-synuclein in PBMCs paralleled the clinical severity of PD and the degeneration of cardiac sympathetic nerves. Basal activity of autophagy can be lower in patients with PD. Alteration of basal autophagy may be a fundamental aspect of PD. (C) 2017 Elsevier Inc. All rights reserved.