一项中国、美国、西班牙科学家合作的研究首次结合多能干细胞和基因组靶向修饰技术揭示了帕金森病神经干细胞随着衰老过程而发生的退行性病变。这一研究成果为诊断、预防与治疗帕金森病提供了新的潜在靶点。

-2012年11月22日《自然》

中文翻译


【题目】致病性LRRK2引起的人神经干细胞的进行性退化

【译文】研究表明核结构缺陷与大量人类疾病和老化的表现相关。因此那些表现与老化相关的疾病可能被联系到核异常出现的理论似乎变得合理了。我们决定通过关注富含亮氨酸重复单位激酶2(LRRK2)的显性突变(G2019S),评价衰老相关疾病条件下的核组织,G2019S突变与家族性和散发性帕金森疾病以及小鼠成熟神经发生的损害相关。本研究报道了帕金森疾病患者来源的诱导多能性干细胞(iPSCs)的产生和人神经干细胞(NSC)群中LRRK2(G2019S)突变的意义。突变的NSC表现出对蛋白酶体压力的敏感性增加,以及核被膜组织、克隆扩增和神经分化的传导依赖的缺陷。通过在帕金森疾病iPSCs中利用其野生型相似物对LRRK2(G2019S)突变的靶向校正使得疾病表型得以恢复,且在人胚胎干细胞中LRRK2(G2019S)突变的靶向敲入后疾病表型发生重演。对人脑部组织分析表明临床上诊断为帕金森疾病的患者中存在核被膜的损害。总之,我们的结果证实了细胞核作为帕金森疾病病理中先前未知的细胞器,并可能有助于为帕金森疾病的诊断及靶向这一基本细胞结构的治疗方法的发展开启新的方向。

英文原稿


[Title]: Progressive degeneration of human neural stem cells caused by pathogenic LRRK2

[Authors]:Guang-Hui Liu,1, 2, 6 Jing Qu,1, 2, 6 Keiichiro Suzuki,2, 6 Emmanuel Nivet,2 Mo Li,2 Nuria Montserrat,3 Fei Yi,2 Xiuling Xu,1 Sergio Ruiz,2 Weiqi Zhang,1 Ulrich Wagner,4 Audrey Kim,4 Bing Ren,4 Ying Li,1 April Goebl,2 Jessica Kim,2 Rupa Devi Soligalla,2 Ilir Dubova,2 James Thompson,5 John Yates III,5 Concepcion Rodriguez Esteban,2 Ignacio Sancho-Martinez2 & Juan Carlos Izpisua Belmonte2, 3

[Abstract]Nuclear-architecture defects have been shown to correlate with the manifestation of a number of human diseases as well as ageing. It is therefore plausible that diseases whose manifestations correlate with ageing might be connected to the appearance of nuclear aberrations over time. We decided to evaluate nuclear organization in the context of ageing-associated disorders by focusing on a leucine-rich repeat kinase 2 (LRRK2) dominant mutation (G2019S; glycine-to-serine substitution at amino acid 2019), which is associated with familial and sporadic Parkinson’s disease as well as impairment of adult neurogenesis in mice5. Here we report on the generation of induced pluripotent stem cells (iPSCs) derived from Parkinson’s disease patients and the implications of LRRK2(G2019S) mutation in human neural-stem-cell (NSC) populations. Mutant NSCs showed increased susceptibility to proteasomal stress as well as passage-dependent deficiencies in nuclear-envelope organization, clonal expansion and neuronal differentiation. Disease phenotypes were rescued by targeted correction of the LRRK2(G2019S) mutation with its wild-type counterpart in Parkinson’s disease iPSCs and were recapitulated after targeted knock-in of the LRRK2(G2019S) mutation in human embryonic stem cells. Analysis of human brain tissue showed nuclear-envelope impairment in clinically diagnosed Parkinson’s disease patients. Together, our results identify the nucleus as a previously unknown cellular organelle in Parkinson’s disease pathology and may help to open new avenues for Parkinson’s disease diagnoses as well as for the potential development of therapeutics targeting this fundamental cell structure.

原文地址

http://www.nature.com/nature/journal/v491/n7425/full/nature11557.html

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