Modeling hallmark pathology using motor neurons derived from the family and sporadic amyotrophic lateral sclerosis patient-specific iPS cells.
Modeling hallmark pathology using motor neurons derived from the family and sporadic amyotrophic lateral sclerosis patient-specific iPS cells.
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DOI：
10.1186/s13287-018-1048-1
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发表时间：
2018-11-15
影响因子：
7.5
通讯作者：
Qian K
中科院分区：
文献类型：
--
作者：
Sun X;Song J;Huang H;Chen H;Qian K
肌萎缩侧索硬化症(ALS)是一种破坏性、进行性、异质性、最常见的运动神经元(MN)疾病。到目前为止，还没有治愈这种疾病的方法。对转基因小鼠的研究已经取得了显著的结果，有助于我们了解ALS的潜在机制。尽管如此，在过去20多年的30多项大型临床试验中，没有一项被证明是成功的，这导致一些研究人员对临床前模型的有效性提出了质疑。将仙台病毒导入成纤维细胞，建立了人诱导多能细胞(IPSCs)。我们通过TALEN介导的同源重组，将CAG-TDP43(G298S)盒或CAG-EGFP盒插入人胚胎干细胞(ESC，H9)的PPP1R12C基因座，建立了TDP-43HES。将IPSCs或HESC分化为运动神经元和非运动神经元作为对照。在不同分化阶段检测到相应的生物标志物。对TDP-43聚集体、神经丝和线粒体进行分析。在这项研究中，我们使用了来自一名携带TDP43 G298S突变的ALS患者和两名散发性ALS患者的IPSCs来源的人MN，结果表明，在存活的MN中，散发性ALS和家族性ALS都具有TDP-43聚集的特征。与野生型(WT)GM15对照组相比，ALSMN组神经丝(NF)包涵体也显著增加(P <； 0.05)。ALS MN组轴突线粒体密度明显低于对照组。将TDP-43 G298S导入人胚胎干细胞的AAVS基因座，获得了患者来源的G289S MN的表型。通过用蛋白酶体抑制剂攻击MNS，我们发现MNS更容易受到MG132的攻击，并伴随着一些表型变化，如TDP43易位、NF包涵体、线粒体分布障碍和caspase3的激活。我们的结果提示，TDP43蛋白的改变、核因子包涵体的改变和线粒体的分布障碍是家族性和散发性ALS常见的早期病理。这些发现将有助于我们深入了解该病的发病机制，并筛选治疗该病的相关药物。本文的在线版本(10.1186/s13287-0181048-1)包含补充材料，可供授权用户使用。
Amyotrophic lateral sclerosis (ALS) represents a devastating, progressive, heterogeneous, and the most common motor neuron (MN) disease. To date, no cure has been available for the condition. Studies with transgenic mice have yielded significant results that help us understand the underlying mechanisms of ALS. Nonetheless, none of more than 30 large clinical trials over the past 20 years proved successful, which led some researchers to challenge the validity of the preclinical models. Human-induced pluripotent cells (iPSCs) were established by introducing Sendai virus into fibroblast cells. We established TDP-43 HES by inserting CAG-TDP43 (G298S) cassette or the CAG-EGFP cassette into PPP1R12C-locus of human embryonic stem cells (ESC, H9) by TALEN-mediated homologous recombination. iPSCs or HESC were differentiated to motor neurons and non-motor neuron as control. Relevant biomarkers were detected in different differentiated stages. TDP-43 aggregates, neurofilament, and mitochondria analyses were performed. In this study, using iPSCs-derived human MN from an ALS patient with a TDP43 G298S mutation and two sporadic ALS patients, we showed that both sporadic and familial ALS were characterized by TDP-43 aggregates in the surviving MN. Significantly higher neurofilament (NF) inclusion was also found in ALS MN compared with wild-type (WT) GM15 controls (P < 0.05). The neurite mitochondria density was significantly lower in ALS MN than that in the control MNs. Transgenesis of TDP-43 G298S into AAVS locus in human embryonic stem cells reproduced phenotype of patient-derived G289S MN. By challenging MNs with a proteasome inhibitor, we found that MNs were more vulnerable to MG132, with some accompanying phenotype changes, such as TDP43 translocation, NF inclusion, mitochondria distribution impairment, and activation of caspase3. Our results suggested that changes in TDP43 protein, NF inclusion, and distribution impairment of mitochondria are common early pathology both in familial and sporadic ALS. These findings will help us gain insight into the pathogenesis of the condition and screen relevant drugs for the disease. The online version of this article (10.1186/s13287-018-1048-1) contains supplementary material, which is available to authorized users.
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DOI：
10.1016/j.mcn.2013.07.007
发表时间：
2013-09
期刊：
Molecular and cellular neurosciences
影响因子：
--
作者：
Burkhardt MF;Martinez FJ;Wright S;Ramos C;Volfson D;Mason M;Garnes J;Dang V;Lievers J;Shoukat-Mumtaz U;Martinez R;Gai H;Blake R;Vaisberg E;Grskovic M;Johnson C;Irion S;Bright J;Cooper B;Nguyen L;Griswold-Prenner I;Javaherian A
通讯作者：
Javaherian A
影响因子：
29
作者：
Freischmidt, Axel;Mueller, Kathrin;Andersen, Peter M.
通讯作者：
Andersen, Peter M.
DOI：
10.1136/jnnp.2009.183525
发表时间：
2010-04
期刊：
Journal of neurology, neurosurgery, and psychiatry
影响因子：
--
作者：
Logroscino G;Traynor BJ;Hardiman O;Chiò A;Mitchell D;Swingler RJ;Millul A;Benn E;Beghi E;EURALS
通讯作者：
EURALS
影响因子：
16.6
作者：
Du, Zhong-Wei;Chen, Hong;Liu, Huisheng;Lu, Jianfeng;Qian, Kun;Huang, CindyTzu-Ling;Zhong, Xiaofen;Fan, Frank;Zhang, Su-Chun
通讯作者：
Zhang, Su-Chun
影响因子：
4.8
作者：
Shahheydari H;Ragagnin A;Walker AK;Toth RP;Vidal M;Jagaraj CJ;Perri ER;Konopka A;Sultana JM;Atkin JD
通讯作者：
Atkin JD