Hou Xu, Watzlawik Jens O, Cook Casey, Liu Chia-Chen, Kang Silvia S, Lin Wen-Lang, DeTure Michael, Heckman Michael G, Diehl Nancy N, Al-Shaikh Fadi S Hanna, Walton Ronald L, Ross Owen A, Melrose Heather L, Ertekin-Taner Nilüfer, Bu Guojun, Petrucelli Leonard, Fryer John D, Murray Melissa E, Dickson Dennis W, Fiesel Fabienne C, Springer Wolfdieter
Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA.
Division of Biomedical Statistics and Informatics, Mayo Clinic, Jacksonville, Florida, USA.
Alzheimers Dement. 2020 Oct 8;17(3):417-30. doi: 10.1002/alz.12198.
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.
具有细胞保护作用的PTEN诱导激酶1（PINK1）-帕金RBR E3泛素蛋白连接酶（PRKN）通路通过磷酸化泛素（pS65-Ub）选择性标记受损线粒体，以便通过自噬将其清除（线粒体自噬）。由于线粒体功能障碍和降解途径异常是阿尔茨海默病（AD）的早期特征，线粒体自噬受损可能参与了其发病机制。
通过生化分析结合组织和单细胞成像，评估AD尸检脑和转基因小鼠模型中线粒体自噬标记物pS65-Ub的形态、水平和分布。
分析显示AD脑中pS65-Ub水平显著升高，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病理无关。单细胞分析显示，根据所分析的脑区不同，pS65-Ub主要与线粒体、GVD小体和/或溶酶体共定位。
我们的研究突出了AD中线粒体自噬的改变与早期tau病理相关，并表明不同的线粒体、自噬和/或溶酶体功能障碍可能导致疾病中的选择性易损性。
