Mitophagy alterations in Alzheimer's disease are associated with granulovacuolar degeneration and early tau pathology.
Mitophagy alterations in Alzheimer's disease are associated with granulovacuolar degeneration and early tau pathology.
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DOI：
10.1002/alz.12198
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发表时间：
2020-10-08
期刊：
影响因子：
--
通讯作者：
Springer W
中科院分区：
文献类型：
--
作者：
Hou X;Watzlawik JO;Cook C;Liu CC;Kang SS;Lin WL;DeTure M;Heckman MG;Diehl NN;Al-Shaikh FSH;Walton RL;Ross OA;Melrose HL;Ertekin-Taner N;Bu G;Petrucelli L;Fryer JD;Murray ME;Dickson DW;Fiesel FC;Springer W
细胞保护性的PTEN诱导的激酶1（PINK 1）-parkin RBR E3泛素蛋白连接酶（PRKN）途径选择性地用磷酸化的泛素（pS 65-Ub）标记受损的线粒体，用于其自噬去除（线粒体自噬）。由于线粒体和降解途径的功能障碍是阿尔茨海默病（AD）的早期特征，线粒体自噬损伤可能有助于发病机制。在AD尸检脑和转基因小鼠模型中，通过生物化学分析结合组织和单细胞成像评价线粒体自噬标签pS 65 ‐Ub的形态、水平和分布。分析显示AD脑中pS 65 ‐Ub水平显著增加，这与颗粒空泡变性（GVD）和早期磷酸化tau沉积密切相关，但与淀粉样β蛋白病理学无关。单细胞分析显示pS 65-Ub与线粒体、GVD体和/或溶酶体的主要共定位，这取决于所分析的脑区域。我们的研究强调了AD中与早期tau病理学相关的线粒体自噬改变，并表明不同的线粒体、自噬和/或溶酶体衰竭可能导致疾病的选择性脆弱性。
The cytoprotective PTEN‐induced kinase 1 (PINK1)‐parkin RBR E3 ubiquitin protein ligase (PRKN) pathway selectively labels damaged mitochondria with phosphorylated ubiquitin (pS65‐Ub) for their autophagic removal (mitophagy). Because dysfunctions of mitochondria and degradation pathways are early features of Alzheimer's disease (AD), mitophagy impairments may contribute to the pathogenesis. Morphology, levels, and distribution of the mitophagy tag pS65‐Ub were evaluated by biochemical analyses combined with tissue and single cell imaging in AD autopsy brain and in transgenic mouse models. Analyses revealed significant increases of pS65‐Ub levels in AD brain, which strongly correlated with granulovacuolar degeneration (GVD) and early phospho‐tau deposits, but were independent of amyloid beta pathology. Single cell analyses revealed predominant co‐localization of pS65‐Ub with mitochondria, GVD bodies, and/or lysosomes depending on the brain region analyzed. Our study highlights mitophagy alterations in AD that are associated with early tau pathology, and suggests that distinct mitochondrial, autophagic, and/or lysosomal failure may contribute to the selective vulnerability in disease.
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DOI：
10.1523/jneurosci.6412-10.2011
发表时间：
2011-05-25
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Lee S;Sato Y;Nixon RA
通讯作者：
Nixon RA
神经元中的自噬诱导和自噬体清除：与阿尔茨海默氏病自噬病理学的关系。
影响因子：
5.3
作者：
Boland, Barry;Kumar, Asok;Lee, Sooyeon;Platt, Frances M.;Wegiel, Jerzy;Yu, W. Haung;Nixon, Ralph A.
通讯作者：
Nixon, Ralph A.
影响因子：
25
作者：
Fu H;Hardy J;Duff KE
通讯作者：
Duff KE
DOI：
10.1083/jcb.201603039
发表时间：
2016-08-01
期刊：
The Journal of cell biology
影响因子：
--
作者：
McWilliams TG;Prescott AR;Allen GF;Tamjar J;Munson MJ;Thomson C;Muqit MM;Ganley IG
通讯作者：
Ganley IG
影响因子：
14.5
作者：
Du, Fang;Yu, Qing;Yan, Shirley ShiDu
通讯作者：
Yan, Shirley ShiDu