Liver-X-receptor agonists rescue axonal degeneration in SPG11-deficient neurons via regulating cholesterol trafficking.
Liver-X-receptor agonists rescue axonal degeneration in SPG11-deficient neurons via regulating cholesterol trafficking.
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DOI：
10.1016/j.nbd.2023.106293
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发表时间：
2023-10-15
影响因子：
6.1
通讯作者：
Li, Xue-Jun
中科院分区：
文献类型：
--
作者：
Chai, Eric;Chen, Zhenyu;Mou, Yongchao;Thakur, Gitika;Zhan, Weihai;Li, Xue-Jun
关键词：
痉挛截瘫11型(SPG11)是一种常见的常染色体隐性遗传性痉挛截瘫(HSP)，其特征是皮质运动神经元轴突变性，导致肌肉痉挛和无力。脂质转运受损是包括SPG11在内的神经退行性疾病的一种新的病理，尽管它在人SPG11神经元轴突变性中的作用尚不清楚。在这里，我们通过敲除人胚胎干细胞(HESCs)中的SPG11基因，建立了一个基于多能干细胞的SPG11模型。这些干细胞随后被分化为皮质投射神经元(PNS)，这是HSP患者受影响的细胞类型，以检查轴突缺陷和胆固醇分布。我们的数据显示，SPG11缺乏导致轴突生长减少，轴突运输受损，并累积肿胀，概括了疾病特异性表型。在SPG11基因敲除的神经元中，胆固醇在溶酶体中积累，在质膜中减少，表明胆固醇运输受到损害。引人注目的是，肝X受体(LXR)激动剂恢复了胆固醇的稳态，导致了SPG11缺陷的皮质PNS随后的轴突缺陷的挽救。为了进一步确定SPG11中胆固醇动态平衡受损的含义，我们检测了SPG11疾病突变敲入hESCs产生的皮质PNS中的胆固醇分布，并观察到类似的胆固醇转运障碍。此外，LXR激动剂挽救了异常的胆固醇分布，减轻了SPG11疾病突变神经元的变性。综上所述，我们的数据显示了SPG11人类神经元轴突变性背后的胆固醇运输受损，并强调了LXR激动剂通过恢复胆固醇稳态来治疗SPG11的潜力。
Spastic paraplegia type 11 (SPG11) is a common autosomal recessive form of hereditary spastic paraplegia (HSP) characterized by the degeneration of cortical motor neuron axons, leading to muscle spasticity and weakness. Impaired lipid trafficking is an emerging pathology in neurodegenerative diseases including SPG11, though its role in axonal degeneration of human SPG11 neurons remains unknown. Here, we established a pluripotent stem cell-based SPG11 model by knocking down the SPG11 gene in human embryonic stem cells (hESCs). These stem cells were then differentiated into cortical projection neurons (PNs), the cell types affected in HSP patients, to examine axonal defects and cholesterol distributions. Our data revealed that SPG11 deficiency led to reduced axonal outgrowth, impaired axonal transport, and accumulated swellings, recapitulating disease-specific phenotypes. In SPG11-knockdown neurons, cholesterol was accumulated in lysosome and reduced in plasma membrane, revealing impairments in cholesterol trafficking. Strikingly, the liver-X-receptor (LXR) agonists restored cholesterol homeostasis, leading to the rescue of subsequent axonal defects in SPG11-deficient cortical PNs. To further determine the implication of impaired cholesterol homeostasis in SPG11, we examined the cholesterol distribution in cortical PNs generated from SPG11 disease-mutation knock-in hESCs, and observed a similar cholesterol trafficking impairment. Moreover, LXR agonists rescued the aberrant cholesterol distribution and mitigated the degeneration of SPG11 disease-mutated neurons. Taken together, our data demonstrate impaired cholesterol trafficking underlying axonal degeneration of SPG11 human neurons, and highlight the therapeutic potential of LXR agonists for SPG11 through restoring cholesterol homeostasis.
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影响因子：
2.5
作者：
Che DL;Chowdary PD;Cui B
通讯作者：
Cui B
影响因子：
3.3
作者：
Hirst J;Borner GH;Edgar J;Hein MY;Mann M;Buchholz F;Antrobus R;Robinson MS
通讯作者：
Robinson MS
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
影响因子：
9.9
作者：
Lauria, G;Morbin, M;Pareyson, D
通讯作者：
Pareyson, D
DOI：
10.1016/b978-0-444-59565-2.00060-5
发表时间：
2013-01-01
期刊：
PEDIATRIC NEUROLOGY, PT III
影响因子：
--
作者：
Denora, Paola S.;Santorelli, Filippo M.;Bertini, Enrico
通讯作者：
Bertini, Enrico