摘要
线粒体微扰如氧化应激,增加分裂/融合功能失调和线粒体自噬是与阿尔茨海默病的特征一致,但是引发这些扰动的机制尚不清楚。线粒体缺陷的一个潜在来源可能是线粒体蛋白平衡不平衡了。在这点上,研究表明当损伤的和未折叠的蛋白在线粒体基质中异常累积的时候,一个特殊的线粒体未折叠蛋白质反应(mtUPR)会被激活,造成关于线粒体稳定的主要基因的正向调节。为了测试未折叠蛋白反应是否在AD中发生,我们对课题中分为散发性AD,家族性AD(与早老素-1突变或者认知完全控制)的死后额叶皮质样品中采用了实时定量PCR。与对照组相比,分散性AD课题中被mtUPR激活的选择基因表达层面表现出一个显著的40%-60%的增,包括线粒体伴侣DNAJA3,Hspd1,、HSPE1、线粒体蛋白酶和yme1l1 CLPP,和txn2,线粒体特异性氧化还原酶。此外,通过比较家族性AD和对照组,所有6mtUPR基因的水平显著上调了70%-90%,这些表达水平显著超过了散发性AD。Hspd1(Hsp60)是通过蛋白印迹法所证实。这些数据证明了散发性和家族性AD的特点是mtUPR基因激活这一观点。了解这种反应的生理后果可能会提供关于AD过程中选择性神经脆弱性或内源性代偿机制的亚细胞机制线索。
关键词: 阿尔茨海默病,线粒体,线粒体自噬,早老素,未折叠蛋白反应
Current Alzheimer Research
Title:Evidence for Mitochondrial UPR Gene Activation in Familial and Sporadic Alzheimer’s Disease
Volume: 13 Issue: 6
Author(s): John S. Beck, Elliott J. Mufson, Scott E. Counts
Affiliation:
关键词: 阿尔茨海默病,线粒体,线粒体自噬,早老素,未折叠蛋白反应
摘要: Mitochondrial perturbations such as oxidative stress, increased fission/fusion dysfunction, and mitophagy are consistent features of Alzheimer’s disease (AD), yet the mechanisms that initiate these perturbations are unclear. One potential source for mitochondrial defects could be an imbalance in mitochondrial proteostasis. In this regard, studies indicate that a specialized mitochondrial unfolded protein response (mtUPR) is activated upon the aberrant accumulation of damaged or unfolded proteins in the mitochondrial matrix, resulting in the up-regulation of key genes involved in mitochondrial stabilization. To test whether mtUPR activation occurs in AD, we performed real-time quantitative PCR on postmortem frontal cortex samples from subjects classified as sporadic AD, familial AD linked to presenilin-1 mutations, or cognitively intact controls. Compared to controls, sporadic AD subjects exhibited a significant ~40-60% increase in expression levels of select genes activated by the mtUPR, including mitochondrial chaperones dnaja3, hspd1, and hspe1, mitochondrial proteases clpp and yme1l1, and txn2, a mitochondrial-specific oxidoreductase. Furthermore, levels of all six mtUPR genes were significantly up-regulated by ~70-90% in familial AD compared to controls, and these expression levels were significantly higher compared to sporadic AD. The increase in hspd1 (Hsp60) was validated by western blotting. These data support the concept that both sporadic and familial AD are characterized by mtUPR gene activation. Understanding the physiological consequences of this response may provide subcellular mechanistic clues to selective neuronal vulnerability or endogenous compensatory mechanisms during the progression of AD.
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John S. Beck, Elliott J. Mufson, Scott E. Counts , Evidence for Mitochondrial UPR Gene Activation in Familial and Sporadic Alzheimer’s Disease, Current Alzheimer Research 2016; 13 (6) . https://dx.doi.org/10.2174/1567205013666151221145445
DOI https://dx.doi.org/10.2174/1567205013666151221145445 |
Print ISSN 1567-2050 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5828 |
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