Accelerating the clearance of mutant huntingtin protein aggregates through autophagy induction by europium hydroxide nanorods.
Accelerating the clearance of mutant huntingtin protein aggregates through autophagy induction by europium hydroxide nanorods.
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DOI：
10.1016/j.biomaterials.2013.10.024
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发表时间：
2014
期刊：
影响因子：
14
通讯作者：
Pengfei Wei;Li Zhang;S. Nethi;A. Barui;Jun Lin;W. Zhou;Yi Shen;N. Man;Yunjiao Zhang;Jing Xu;C. Patra;L. Wen
中科院分区：
文献类型：
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作者：
Pengfei Wei;Li Zhang;S. Nethi;A. Barui;Jun Lin;W. Zhou;Yi Shen;N. Man;Yunjiao Zhang;Jing Xu;C. Patra;L. Wen
自噬是促进蛋白质聚集体清除的重要途径之一，有助于神经退行性疾病的治疗。尽管有许多报道证明了用小分子（包括雷帕霉素、海藻糖和锂）诱导自噬，然而，很少有报道提到通过纳米颗粒诱导自噬来清除易聚集蛋白。在这篇文章中，我们已经证明，氢氧化铕[EuIII（OH）3]纳米棒可以减少亨廷顿蛋白质聚集（带有74个polyQ重复的EGFP标记的亨廷顿蛋白质），这是神经退行性疾病的原因。我们再次发现，这些纳米棒通过表达更高水平的特征性自噬标志物蛋白LC 3-II和降解选择性自噬底物/货物受体p62/SQSTM 1，在不同的细胞系（Neuro 2a，PC 12和HeLa细胞）中诱导真实的自噬通量。此外，通过使用特异性抑制剂（渥曼青霉素和氯喹）也观察到通过自噬阻断对蛋白质聚集清除的抑制，表明自噬参与亨廷顿蛋白质聚集的降解。由于[EuIII（OH）3]纳米棒可以通过自噬诱导增强亨廷顿蛋白聚集体的降解，我们坚信这些纳米棒将在不久的将来用于开发各种神经退行性疾病的治疗策略。
Autophagy is one of the well-known pathways to accelerate the clearance of protein aggregates, which contributes to the therapy of neurodegenerative diseases. Although there are numerous reports that demonstrate the induction of autophagy with small molecules including rapamycin, trehalose and lithium, however, there are few reports mentioning the clearance of aggregate-prone proteins through autophagy induction by nanoparticles. In the present article, we have demonstrated that europium hydroxide [EuIII(OH)3] nanorods can reduce huntingtin protein aggregation (EGFP-tagged huntingtin protein with 74 polyQ repeats), responsible for neurodegenerative diseases. Again, we have found that these nanorods induce authentic autophagy flux in different cell lines (Neuro 2a, PC12 and HeLa cells) through the expression of higher levels of characteristic autophagy marker protein LC3-II and degradation of selective autophagy substrate/cargo receptor p62/SQSTM1. Furthermore, depression of protein aggregation clearance through the autophagy blockade has also been observed by using specific inhibitors (wortmannin and chloroquine), indicating that autophagy is involved in the degradation of huntingtin protein aggregation. Since [EuIII(OH)3] nanorods can enhance the degradation of huntingtin protein aggregation via autophagy induction, we strongly believe that these nanorods would be useful for the development of therapeutic treatment strategies for various neurodegenerative diseases in near future using nanomedicine approach.