Junior Research Group Synaptic Plasticity, Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany ; Graduate School of Cellular & Molecular Neuroscience, University of Tübingen, Tübingen, Germany.
Junior Research Group Synaptic Plasticity, Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
PLoS One. 2013 Dec 30;8(12):e83714. doi: 10.1371/journal.pone.0083714. eCollection 2013.
Mortalin is an essential component of the molecular machinery that imports nuclear-encoded proteins into mitochondria, assists in their folding, and protects against damage upon accumulation of dysfunctional, unfolded proteins in aging mitochondria. Mortalin dysfunction associated with Parkinson's disease (PD) increases the vulnerability of cultured cells to proteolytic stress and leads to changes in mitochondrial function and morphology. To date, Drosophila melanogaster has been successfully used to investigate pathogenesis following the loss of several other PD-associated genes. We generated the first loss-of-Hsc70-5/mortalin-function Drosophila model. The reduction of Mortalin expression recapitulates some of the defects observed in the existing Drosophila PD-models, which include reduced ATP levels, abnormal wing posture, shortened life span, and reduced spontaneous locomotor and climbing ability. Dopaminergic neurons seem to be more sensitive to the loss of mortalin than other neuronal sub-types and non-neuronal tissues. The loss of synaptic mitochondria is an early pathological change that might cause later degenerative events. It precedes both behavioral abnormalities and structural changes at the neuromuscular junction (NMJ) of mortalin-knockdown larvae that exhibit increased mitochondrial fragmentation. Autophagy is concomitantly up-regulated, suggesting that mitochondria are degraded via mitophagy. Ex vivo data from human fibroblasts identifies increased mitophagy as an early pathological change that precedes apoptosis. Given the specificity of the observed defects, we are confident that the loss-of-mortalin model presented in this study will be useful for further dissection of the complex network of pathways that underlie the development of mitochondrial parkinsonism.
线粒体蛋白 2（Mortalin）是一种重要的分子机器组成部分，可将核编码蛋白导入线粒体，协助其折叠，并在衰老线粒体中功能失调和未折叠蛋白质积累时防止损伤。与帕金森病（PD）相关的 Mortalin 功能障碍会增加培养细胞对蛋白水解应激的易感性，并导致线粒体功能和形态发生变化。迄今为止，黑腹果蝇已成功用于研究几种其他与 PD 相关基因缺失后的发病机制。我们生成了首个丧失 Hsc70-5/Mortalin 功能的果蝇模型。Mortalin 表达的减少再现了一些现有的果蝇 PD 模型中观察到的缺陷，包括降低的 ATP 水平、异常的翅膀姿势、寿命缩短以及自发运动和攀爬能力降低。多巴胺能神经元似乎比其他神经元亚型和非神经元组织对 Mortalin 的缺失更为敏感。突触线粒体的丢失是一种早期的病理变化，可能导致随后的退行性事件。它先于 Mortalin 敲低幼虫的行为异常和神经肌肉接头（NMJ）的结构变化，后者表现出线粒体碎片化增加。自噬同时被上调，表明线粒体通过线粒体自噬被降解。来自人成纤维细胞的体外数据表明，线粒体自噬增加是一种早期的病理变化，先于细胞凋亡。鉴于观察到的缺陷的特异性，我们有信心，本研究中提出的丧失 Mortalin 模型将有助于进一步剖析导致线粒体帕金森病发展的复杂途径网络。
