Chenodeoxycholic acid rescues axonal degeneration in induced pluripotent stem cell-derived neurons from spastic paraplegia type 5 and cerebrotendinous xanthomatosis patients.
Chenodeoxycholic acid rescues axonal degeneration in induced pluripotent stem cell-derived neurons from spastic paraplegia type 5 and cerebrotendinous xanthomatosis patients.
复制标题
鹅去氧胆酸挽救5型痉挛截瘫和脑腱黄瘤病患者诱导的多能干细胞来源的神经元的轴突变性。
DOI：
10.1186/s13023-023-02666-w
复制
发表时间：
2023-04-06
影响因子：
3.7
通讯作者：
中科院分区：
文献类型：
--
作者：
调节胆固醇和胆汁酸代谢的两个关键基因CYP27A1和CYP7B1的双等位基因突变分别导致脑腱黄瘤病（CTX）和遗传性痉挛性截瘫5型（SPG5）。这些罕见疾病以皮质脊髓运动神经元轴突进行性变性为特征，但其潜在的致病机制和减轻轴突变性的策略仍不清楚。为了生成基于诱导多能干细胞（iPSC）的CTX和SPG5模型，我们将患者皮肤成纤维细胞用含有多能因子的表皮载体转导成纤维细胞，将其重编程为iPSC。这些患者特异性iPSCs以及对照iPSCs分化为皮质投射神经元（PNs），并检查生化改变和疾病相关表型。CTX和SPG5患者ipsc衍生的皮质PNs再现了两种疾病的几种疾病特异性生化变化和轴突缺陷。值得注意的是，胆汁酸鹅去氧胆酸（CDCA）有效地减轻了患者ipsc来源神经元的生化改变并挽救了轴突变性。为了进一步研究潜在的疾病机制，我们使用crispr -cas9介导的基因编辑技术开发了CYP7B1敲除的人胚胎干细胞（hESC）系，并在分化后检测了hESC衍生的皮质PNs。敲除CYP7B1导致人类皮质PN轴突出现类似的轴突囊泡和变性，证实了基因缺失与轴突变性之间的因果关系。有趣的是，CYP7B1缺乏导致神经丝表达和组织受损以及轴突变性，CDCA可以挽救这一缺陷，从而建立了新的疾病机制和治疗靶点，以减轻轴突变性。我们的数据证明了基于人类多能干细胞的CTX和SPG5神经元模型中的疾病特异性脂质紊乱和轴突病变机制，并确定了CDCA（一种成熟的CTX治疗方法）作为SPG5的潜在药物治疗方法。我们提出这种新的治疗策略来挽救SPG5轴突变性，这是一种目前无法治愈的疾病。在线版本包含补充材料，下载地址为10.1186/s13023-023-02666-w。
Biallelic mutations in CYP27A1 and CYP7B1, two critical genes regulating cholesterol and bile acid metabolism, cause cerebrotendinous xanthomatosis (CTX) and hereditary spastic paraplegia type 5 (SPG5), respectively. These rare diseases are characterized by progressive degeneration of corticospinal motor neuron axons, yet the underlying pathogenic mechanisms and strategies to mitigate axonal degeneration remain elusive. To generate induced pluripotent stem cell (iPSC)-based models for CTX and SPG5, we reprogrammed patient skin fibroblasts into iPSCs by transducing fibroblast cells with episomal vectors containing pluripotency factors. These patient-specific iPSCs, as well as control iPSCs, were differentiated into cortical projection neurons (PNs) and examined for biochemical alterations and disease-related phenotypes. CTX and SPG5 patient iPSC-derived cortical PNs recapitulated several disease-specific biochemical changes and axonal defects of both diseases. Notably, the bile acid chenodeoxycholic acid (CDCA) effectively mitigated the biochemical alterations and rescued axonal degeneration in patient iPSC-derived neurons. To further examine underlying disease mechanisms, we developed CYP7B1 knockout human embryonic stem cell (hESC) lines using CRISPR-cas9-mediated gene editing and, following differentiation, examined hESC-derived cortical PNs. Knockout of CYP7B1 resulted in similar axonal vesiculation and degeneration in human cortical PN axons, confirming a cause-effect relationship between gene deficiency and axonal degeneration. Interestingly, CYP7B1 deficiency led to impaired neurofilament expression and organization as well as axonal degeneration, which could be rescued with CDCA, establishing a new disease mechanism and therapeutic target to mitigate axonal degeneration. Our data demonstrate disease-specific lipid disturbances and axonopathy mechanisms in human pluripotent stem cell-based neuronal models of CTX and SPG5 and identify CDCA, an established treatment of CTX, as a potential pharmacotherapy for SPG5. We propose this novel treatment strategy to rescue axonal degeneration in SPG5, a currently incurable condition. The online version contains supplementary material available at 10.1186/s13023-023-02666-w.
登录
查看更多内容
DOI：
10.1016/j.apsb.2014.12.009
发表时间：
2015-03
期刊：
Acta pharmaceutica Sinica. B
影响因子：
--
作者：
Kwong E;Li Y;Hylemon PB;Zhou H
通讯作者：
Zhou H
影响因子：
158.5
作者：
BERGINER, VM;SALEN, G;SHEFER, S
通讯作者：
SHEFER, S
影响因子：
9.9
作者：
Lauria, G;Morbin, M;Pareyson, D
通讯作者：
Pareyson, D
影响因子：
4.5
作者：
De Pace, Raffaella;Skirzewski, Miguel;Bonifacino, Juan S.
通讯作者：
Bonifacino, Juan S.
影响因子：
5.2
作者：
Denton, Kyle R.;Lei, Ling;Grenier, Jeremy;Rodionov, Vladimir;Blackstone, Craig;Li, Xue-Jun
通讯作者：
Li, Xue-Jun