Ma Kai-Li, Song Lian-Kun, Yuan Yu-He, Zhang Ying, Han Ning, Gao Kai, Chen Nai-Hong
State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Department of Pharmacology, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, PR China; Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Kunming 650118, PR China.
State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Department of Pharmacology, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, PR China.
Neuropharmacology. 2014 Jul;82:132-42. doi: 10.1016/j.neuropharm.2013.07.035. Epub 2013 Aug 21.
α-Synuclein (α-syn), a 14 kDa pre-synaptic protein, is widely involved in the Parkinson's disease (PD) pathogenesis. Recent studies have shown that the nuclear accumulation of α-syn might have a toxic effect. The main purpose of the present study was to explore which amino acid residues in α-syn are associated with its nuclear accumulation, the molecule(s) mediated the nuclear import of α-syn, and the role of α-syn accumulated in the nucleus. It has been noted that the nuclear import of α-syn may be mediated by importin α and that both the amino acid residues 1-60 and 103-140 of α-syn were indispensable for its nuclear import. After imported into the nucleus, the accumulated α-syn played a toxic role in both the PC12 cells and the C57 mice. Furthermore, α-syn-nuclear localization signal-injected mice showed behavioral symptoms associated with PD. Further studies performed in vitro showed that the toxicity of α-syn in the nucleus might be due to an interference of the cell cycle. Thus, it can be concluded that α-syn can accumulate in nucleus, which is mediated by importin α, and promote neurotoxicity by accelerating the cell cycle.
α-突触核蛋白（α-syn）是一种14 kDa的突触前蛋白，广泛参与帕金森病（PD）的发病机制。最近的研究表明，α-syn的核内积累可能具有毒性作用。本研究的主要目的是探索α-syn中哪些氨基酸残基与其核内积累相关，介导α-syn核输入的分子，以及α-syn在细胞核中积累的作用。已经注意到，α-syn的核输入可能由输入蛋白α介导，并且α-syn的1-60和103-140氨基酸残基对其核输入都是必不可少的。导入细胞核后，积累的α-syn在PC12细胞和C57小鼠中均发挥毒性作用。此外，注射α-突触核蛋白核定位信号的小鼠表现出与PD相关的行为症状。体外进一步研究表明，α-syn在细胞核中的毒性可能是由于细胞周期的干扰。因此，可以得出结论，α-syn可以在细胞核中积累，这是由输入蛋白α介导的，并通过加速细胞周期促进神经毒性。
