Disease-associated tau impairs mitophagy by inhibiting Parkin translocation to mitochondria
Disease-associated tau impairs mitophagy by inhibiting Parkin translocation to mitochondria
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DOI：
10.15252/embj.201899360
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发表时间：
2019-02-01
期刊：
影响因子：
11.4
通讯作者：
Goetz, Juergen
中科院分区：
文献类型：
--
作者：
Cummins, Nadia;Tweedie, Andrea;Goetz, Juergen
Tau蛋白的积累是阿尔茨海默病和其他tau病的特征，包括携带致病性tau突变的家族性额颞叶痴呆(FTD)。这些疾病的另一个显著特征是功能失调的线粒体的积累。虽然与疾病相关的tau已知会损害线粒体功能的几个方面，但目前仍不清楚它是否也直接影响线粒体的质量控制，特别是Parkin依赖的有丝分裂。利用mito-QC有丝分裂吞噬报告基因，我们发现人野生型(HTau)和ftd突变体tau(HP301L)都通过减少Parkin的线粒体易位而抑制了神经母细胞瘤细胞的有丝分裂吞噬。在秀丽线虫的神经系统中，hTau的表达降低了丝裂原吞噬作用，而hP301L的表达则完全抑制了它。这些影响不是由于线粒体膜电位或细胞骨架的变化，因为tau通过将有缺陷的线粒体隔离在细胞质中而特别地损害了Parkin对有缺陷的线粒体的募集。这种隔离是由Parkin与tau的投影域的异常相互作用所介导的。由于线粒体在神经退行性疾病中功能失调，这些数据表明这是一个恶性循环，tau也抑制了受损线粒体的降解。
Accumulation of the protein tau characterises Alzheimer's disease and other tauopathies, including familial forms of frontotemporal dementia (FTD) that carry pathogenic tau mutations. Another hallmark feature of these diseases is the accumulation of dysfunctional mitochondria. Although disease-associated tau is known to impair several aspects of mitochondrial function, it is still unclear whether it also directly impinges on mitochondrial quality control, specifically Parkin-dependent mitophagy. Using the mito-QC mitophagy reporter, we found that both human wild-type (hTau) and FTD mutant tau (hP301L) inhibited mitophagy in neuroblastoma cells, by reducing mitochondrial translocation of Parkin. In the Caenorhabditis elegans nervous system, hTau expression reduced mitophagy, whereas hP301L expression completely inhibited it. These effects were not due to changes in the mitochondrial membrane potential or the cytoskeleton, as tau specifically impaired Parkin recruitment to defective mitochondria by sequestering it in the cytosol. This sequestration was mediated by aberrant interactions of Parkin with the projection domain of tau. As mitochondria are dysfunctional in neurodegenerative conditions, these data suggest a vicious cycle, with tau also inhibiting the degradation of damaged mitochondria.