Progressive degeneration of human neural stem cells caused by pathogenic LRRK2.
Progressive degeneration of human neural stem cells caused by pathogenic LRRK2.
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DOI：
10.1038/nature11557
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发表时间：
2012-11-22
期刊：
影响因子：
64.8
通讯作者：
Izpisua Belmonte, Juan Carlos
中科院分区：
文献类型：
--
作者：
Liu, Guang-Hui;Qu, Jing;Suzuki, Keiichiro;Nivet, Emmanuel;Li, Mo;Montserrat, Nuria;Yi, Fei;Xu, Xiuling;Ruiz, Sergio;Zhang, Weiqi;Wagner, Ulrich;Kim, Audrey;Ren, Bing;Li, Ying;Goebl, April;Kim, Jessica;Soligalla, Rupa Devi;Dubova, Ilir;Thompson, James;Yates, John, III;Esteban, Concepcion Rodriguez;Sancho-Martinez, Ignacio;Izpisua Belmonte, Juan Carlos
核结构缺陷已被证明与许多人类疾病的表现以及衰老相关。因此，随着时间的推移，表现与衰老相关的疾病可能与核畸变的出现有关，这是合理的。我们决定在衰老相关疾病的背景下评估核组织，重点关注富含亮氨酸重复激酶2（LRRK 2）显性突变（G2019 S），该突变与家族性和散发性帕金森病（PD）以及小鼠成年神经发生受损有关。在这里，我们报告了PD患者来源的诱导多能干细胞（iPSC）的产生以及LRRK 2（G2019 S）在人类神经干细胞（NSC）群体中的意义。突变的神经干细胞表现出对蛋白酶体应激的敏感性增加，以及克隆扩增和神经元分化中的依赖性缺陷。通过在PD-iPSC中用其野生型对应物靶向校正LRRK 2（G2019 S）突变来挽救疾病表型，并且在人胚胎干细胞（hESC）中靶向敲入LRRK 2（G2019 S）后重现疾病表型。对人脑组织的分析显示，临床诊断的帕金森病患者的核膜受损。总而言之，我们的研究结果将细胞核确定为帕金森病病理学中以前未知的细胞器，并可能有助于为PD诊断开辟新的途径，以及针对这种基本细胞结构的治疗方法的潜在发展。
Nuclear architecture defects have been shown to correlate with the manifestation of a number of human diseases as well as aging. It is then plausible that diseases whose manifestations correlate with aging might be connected to the appearance of nuclear aberrations over time. We decided to evaluate nuclear organization in the context of aging-associated disorders by focusing on a Leucine Rich Repeat Kinase 2 (LRRK2) dominant mutation (G2019S) shown to associate with familial and sporadic Parkinson’s Disease (PD), as well as impairment of adult neurogenesis in mice. Here, we report on the generation of PD patient-derived induced pluripotent stem cells (iPSCs) and the implications of LRRK2(G2019S) in human neural stem cell (NSC) populations. Mutant NSCs showed increased susceptibility to proteasomal stress as well as passage-dependent deficiencies in clonal expansion and neuronal differentiation. Disease phenotypes were rescued by targeted correction of the LRRK2(G2019S) mutation with its wild-type counterpart in PD-iPSCs and recapitulated upon targeted knock-in of LRRK2(G2019S) in human embryonic stem cells (hESCs). Analysis of human brain tissue showed nuclear envelope impairment in clinically diagnosed Parkinson’s patients. Altogether, our results identify the nucleus as a previously unknown cellular organelle in Parkinson’s pathology and may help open new avenues for PD diagnoses as well as potential development of therapeutics targeting this fundamental cell structure.
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影响因子：
3.5
作者：
Kanao, Tomoko;Venderova, Katerina;Imai, Yuzuru
通讯作者：
Imai, Yuzuru
影响因子：
23.9
作者：
Liu, Guang-Hui;Suzuki, Keiichiro;Qu, Jing;Sancho-Martinez, Ignacio;Yi, Fei;Li, Mo;Kumar, Sachin;Nivet, Emmanuel;Kim, Jessica;Soligalla, Rupa Devi;Dubova, Ilir;Goebl, April;Plongthongkum, Nongluk;Fung, Ho-Lim;Zhang, Kun;Loring, Jeanne F.;Laurent, Louise C.;Izpisua Belmonte, Juan Carlos
通讯作者：
Izpisua Belmonte, Juan Carlos
DOI：
10.1073/pnas.0806976105
发表时间：
2008-09-16
影响因子：
11.1
作者：
Suzuki, Keiichiro;Mitsui, Kaoru;Mitani, Kohnosuke
通讯作者：
Mitani, Kohnosuke
影响因子：
9.9
作者：
Thaler, Avner;Mirelman, Anat;Giladi, Nir
通讯作者：
Giladi, Nir
影响因子：
64.8
作者：
Liu, Guang-Hui;Barkho, Basam Z.;Ruiz, Sergio;Diep, Dinh;Qu, Jing;Yang, Sheng-Lian;Panopoulos, Athanasia D.;Suzuki, Keiichiro;Kurian, Leo;Walsh, Christopher;Thompson, James;Boue, Stephanie;Fung, Ho Lim;Sancho-Martinez, Ignacio;Zhang, Kun;Yates, John, III;Izpisua Belmonte, Juan Carlos
通讯作者：
Izpisua Belmonte, Juan Carlos