PARK2 enhancement is able to compensate mitophagy alterations found in sporadic Alzheimer's disease
PARK2 enhancement is able to compensate mitophagy alterations found in sporadic Alzheimer's disease
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DOI：
10.1093/hmg/ddv616
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发表时间：
2016-02-15
影响因子：
3.5
通讯作者：
Garcia-Escudero, Vega
中科院分区：
文献类型：
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作者：
Martin-Maestro, Patricia;Gargini, Ricardo;Garcia-Escudero, Vega
线粒体异常先前已在患者的脑和外周组织中报道，表明它们与散发性阿尔茨海默病（AD）相关。目前的工作评估线粒体功能和人类成纤维细胞和脑活检的回收。使用患者皮肤成纤维细胞的功能研究显示，线粒体损伤后线粒体膜电位恢复较慢，溶酶体和自噬发生变化，伴随着氧化和泛素化蛋白质的增加。在这些细胞中，由于PARK2减少和囊泡诱导不足，积累去极化的线粒体和PINK1，已经证明线粒体自噬受损。增加的Delta 1 PINK1片段水平表明对PARK2易位到线粒体的抑制作用，导致活化的PINK1的积累。此外，PARK2的过表达减少了泛素化蛋白的积累，提高了其对线粒体的靶向作用，并增强了自噬囊泡的合成。这允许线粒体自噬失败的逆转，反映在膜电位的恢复以及PINK 1和线粒体积累的减少。散发性AD成纤维细胞表现出与疾病早期患者海马样本中发现的变化相似的变化，其中PINK 1和Delta 1 PINK 1积累以及线粒体含量异常增加。我们的研究结果表明，线粒体自噬改变可以被认为是一个新的标志散发性AD和验证使用成纤维细胞建模这种病理。
Mitochondrial anomalies have been previously reported in patients' brain and peripheral tissue, suggesting their relevance in sporadic Alzheimer's disease (AD). The present work evaluates mitochondrial function and recycling in human fibroblasts and brain biopsies. Functional studies using patients' skin fibroblasts showed slower mitochondrial membrane potential recovery after a mitochondrial insult together with alterations in lysosomes and autophagy, accompanied by an increase of oxidized and ubiquitinated proteins. Impairment in mitophagy has been proven in these cells due to diminished PARK2 and insufficient vesicle induction, accumulating depolarized mitochondria and PINK1. Augmented Delta 1 PINK1 fragment levels suggest an inhibitory effect over PARK2 translocation to the mitochondria, causing the accumulation of activated PINK1. Moreover, the overexpression of PARK2 diminished ubiquitinated proteins accumulation, improves its targeting to mitochondria and potentiates autophagic vesicle synthesis. This allows the reversion of mitophagy failure reflected in the recovery of membrane potential and the decrease of PINK1 and mitochondria accumulation. Sporadic AD fibroblasts exhibited alterations similar to what it could be found in patients' hippocampal samples at early stages of the disease, where there was an accumulation of PINK1 and Delta 1 PINK1 together with abnormally increased mitochondrial content. Our findings indicate that mitophagy alterations can be considered a new hallmark of sporadic AD and validate the use of fibroblasts for modelling this pathology.