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Progressive degeneration of human neural stem cells caused by pathogenic LRRK2

机译：致病性LRRK2导致人神经干细胞进行性变性

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摘要

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 mice. 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.
机译：核建筑缺陷已被证明与许多人类疾病以及衰老有关。因此，随着时间的流逝，其表现与衰老有关的疾病可能与核像差的出现有关。我们决定通过关注富含亮氨酸的重复激酶2（LRRK2）显性突变（G2019S;氨基酸至2019年的甘氨酸-丝氨酸取代）来评估与衰老相关的疾病的核组织，该突变与家族和散发性帕金森氏病以及小鼠成年神经发生受损。在这里，我们报道了衍生自帕金森氏病患者的诱导性多能干细胞（iPSC）的产生，以及人类神经干细胞（NSC）人群中LRRK2（G2019S）突变的影响。突变的NSC显示出对蛋白酶体应激的敏感性增加，以及核包膜组织，克隆扩增和神经元分化中与传代相关的缺陷。通过对帕金森氏病iPSCs中的野生型对应物进行LRRK2（G2019S）突变的靶向纠正来挽救疾病表型，并在人类胚胎干细胞中定向敲除LRRK2（G2019S）突变后重新概括。对人脑组织的分析显示，在临床确诊的帕金森氏病患者中，核膜被破坏。总之，我们的研究结果确定了核是帕金森氏病病理学中以前未知的细胞器，并可能有助于为帕金森氏病的诊断以及针对这种基本细胞结构的疗法的潜在发展开辟新途径。

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  • 来源
    《Nature》 |2012年第7425期|p.603-607|共5页
  • 作者

    Guang-Hui Liu; JingQu; Keiichiro Suzuki; Emmanuel Nivet; Mo Li; Nuria Montserrat; FeiYi; Xiuling Xu; Sergio Ruiz; Weiqi Zhang; Ulrich Wagner; Audrey Kim; Bing Ren; Ying Li; April Goebl; Jessica Kim; Rupa Devi Soligalla; Ilir Dubova; James Thompson; John Yates III; Concepcion Rodriguez Esteban; Ignacio Sancho-Martinez; Juan Carlos Izpisua Belmonte;

  • 作者单位

    National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China,Gene Expression Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA;

    National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China,Gene Expression Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA;

    Gene Expression Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA;

    Gene Expression Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA;

    Gene Expression Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA;

    Center for Regenerative Medicine in Barcelona, Doctor Aiguader 88,08003 Barcelona, Spain;

    Gene Expression Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA;

    National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China;

    Gene Expression Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA;

    National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China;

    Department of Cellular and Molecular Medicine, Ludwig Institute for Cancer Research, University of California, San Diego School of Medicine, La Jol la,California 92093-0653, USA;

    Department of Cellular and Molecular Medicine, Ludwig Institute for Cancer Research, University of California, San Diego School of Medicine, La Jol la,California 92093-0653, USA;

    Department of Cellular and Molecular Medicine, Ludwig Institute for Cancer Research, University of California, San Diego School of Medicine, La Jol la,California 92093-0653, USA;

    National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China;

    Gene Expression Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA;

    Gene Expression Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA;

    Gene Expression Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA;

    Gene Expression Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA;

    Departmentof Cell Biology, Scripps Research Institute, La Jolla, California 92037, USA;

    Departmentof Cell Biology, Scripps Research Institute, La Jolla, California 92037, USA;

    Gene Expression Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA;

    Gene Expression Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA;

    Gene Expression Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA,Center for Regenerative Medicine in Barcelona, Doctor Aiguader 88,08003 Barcelona, Spain;

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