Mutant huntingtin aggregates impair mitochondrial movement and trafficking in cortical neurons
Mutant huntingtin aggregates impair mitochondrial movement and trafficking in cortical neurons
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DOI：
10.1016/j.nbd.2005.12.007
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发表时间：
2006-05-01
影响因子：
6.1
通讯作者：
Reynolds, IJ
中科院分区：
文献类型：
--
作者：
Chang, DTW;Rintoula, GL;Reynolds, IJ
亨廷顿病(HD)是一种由亨廷顿蛋白基因(Htt)中的多谷氨酰胺重复序列引起的神经退行性疾病。线粒体缺陷和蛋白质聚集体是受影响神经元的特征。最近的研究表明，这些聚集体通过与细胞骨架组件和分子马达相互作用，损害了细胞的运输机制。在这里，我们研究了突变型Htt是否改变了初级皮质神经元中线粒体的运输和形态。我们证明了全长突变体Htt在阻止线粒体运动方面比N端突变体Htt更有效，这一效果与其在胞浆中的高表达有关。聚集体损害了线粒体沿着神经元突起的通道，导致线粒体在聚集体附近聚集并被固定。此外，线粒体交易特别是在聚集体位置减少，而在缺乏聚集体的区域保持不变。我们的结论是，在皮质神经元中，HD病理生理学的早期事件是由胞浆Htt聚集体引起的线粒体的异常移动和运输。(C)2005 Elsevier Inc.保留所有权利。
Huntington's disease (HD) is a neurodegenerative disorder caused by a polyglutamine repeat in the huntingtin gene (Htt). Mitochondrial defects and protein aggregates are characteristic of affected neurons. Recent studies suggest that these aggregates impair cellular transport mechanisms by interacting with cytoskeletal components and molecular motors. Here, we investigated whether mutant Htt alters mitochondrial trafficking and morphology in primary cortical neurons. We demonstrate that full-length mutant Htt was more effective than N-terminal mutant Htt in blocking mitochondrial movement, an effect that correlated with its heightened expression in the cytosolic compartment. Aggregates impaired the passage of mitochondria along neuronal processes, causing mitochondria to accumulate adjacent to aggregates and become immobilized. Furthermore, mitochondrial trafficking was reduced specifically at sites of aggregates while remaining unaltered in regions lacking aggregates. We conclude that in cortical neurons, an early event in HD pathophysiology is the aberrant mobility and trafficking of mitochondria caused by cytosolic Htt aggregates. (c) 2005 Elsevier Inc. All rights reserved.