Mitochondrial mislocalization underlies Abeta42-induced neuronal dysfunction in a Drosophila model of Alzheimer's disease.
Mitochondrial mislocalization underlies Abeta42-induced neuronal dysfunction in a Drosophila model of Alzheimer's disease.
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DOI：
10.1371/journal.pone.0008310
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发表时间：
2009-12-15
期刊：
影响因子：
3.7
通讯作者：
Iijima K
中科院分区：
文献类型：
--
作者：
Iijima-Ando K;Hearn SA;Shenton C;Gatt A;Zhao L;Iijima K
淀粉样蛋白β 42（Aβ42）被认为在阿尔茨海默病（AD）的发病机制中起核心作用。然而，Aβ42诱导神经元功能障碍和变性的分子机制仍不清楚。线粒体功能障碍与AD脑有关。线粒体功能障碍是否仅仅是AD病理学的结果，还是AD发病机制中的早期精液事件仍有待确定。在这里，我们发现Aβ42诱导线粒体错误定位，这有助于Aβ42诱导的转基因果蝇模型中的神经元功能障碍。在Aβ42果蝇脑中，轴突和树突中的线粒体减少，并积聚在胞体中，而没有严重的线粒体损伤或神经变性。相比之下，组织的微管或全球轴突运输没有显着改变，在这个阶段。Aβ42诱导的行为缺陷因线粒体转运的遗传减少而加剧，并受cAMP水平和PKA活性的调节。在Aβ42果蝇脑中，推定的PKA底物磷蛋白水平降低。重要的是，神经元中线粒体转运的扰动足以破坏PKA信号传导并诱导迟发型行为缺陷，这表明线粒体错误定位有助于Aβ42诱导的神经元功能障碍的机制。这些结果表明，线粒体的错误定位是Aβ42体内致病作用的基础。
The amyloid-β 42 (Aβ42) is thought to play a central role in the pathogenesis of Alzheimer's disease (AD). However, the molecular mechanisms by which Aβ42 induces neuronal dysfunction and degeneration remain elusive. Mitochondrial dysfunctions are implicated in AD brains. Whether mitochondrial dysfunctions are merely a consequence of AD pathology, or are early seminal events in AD pathogenesis remains to be determined. Here, we show that Aβ42 induces mitochondrial mislocalization, which contributes to Aβ42-induced neuronal dysfunction in a transgenic Drosophila model. In the Aβ42 fly brain, mitochondria were reduced in axons and dendrites, and accumulated in the somata without severe mitochondrial damage or neurodegeneration. In contrast, organization of microtubule or global axonal transport was not significantly altered at this stage. Aβ42-induced behavioral defects were exacerbated by genetic reductions in mitochondrial transport, and were modulated by cAMP levels and PKA activity. Levels of putative PKA substrate phosphoproteins were reduced in the Aβ42 fly brains. Importantly, perturbations in mitochondrial transport in neurons were sufficient to disrupt PKA signaling and induce late-onset behavioral deficits, suggesting a mechanism whereby mitochondrial mislocalization contributes to Aβ42-induced neuronal dysfunction. These results demonstrate that mislocalization of mitochondria underlies the pathogenic effects of Aβ42 in vivo.
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影响因子：
3.7
作者：
Iijima K;Chiang HC;Hearn SA;Hakker I;Gatt A;Shenton C;Granger L;Leung A;Iijima-Ando K;Zhong Y
通讯作者：
Zhong Y
DOI：
10.1083/jcb.200601067
发表时间：
2006-05-22
期刊：
The Journal of cell biology
影响因子：
--
作者：
Glater EE;Megeath LJ;Stowers RS;Schwarz TL
通讯作者：
Schwarz TL
影响因子：
3.3
作者：
Cao, Weihuan;Song, Ho-Juhn;Konsolaki, Mary
通讯作者：
Konsolaki, Mary
影响因子：
11.4
作者：
Araki, Yoichi;Kawano, Takanori;Suzuki, Toshiharu
通讯作者：
Suzuki, Toshiharu
影响因子：
15.9
作者：
Gong, B;Vitolo, OV;Arancio, O
通讯作者：
Arancio, O