GSK3ß-dependent dysregulation of neurodevelopment in SPG11-patient induced pluripotent stem cell model.
GSK3ß-dependent dysregulation of neurodevelopment in SPG11-patient induced pluripotent stem cell model.
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SPG11患者诱导的多能干细胞模型中神经发育的GSK3 β依赖性失调。
DOI：
10.1002/ana.24633
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发表时间：
2016-05
影响因子：
11.2
通讯作者：
Winner, Beate
中科院分区：
文献类型：
--
作者：
Mishra, Himanshu K.;Prots, Iryna;Havlicek, Steven;Kohl, Zacharias;Perez-Branguli, Francesc;Boerstler, Tom;Anneser, Lukas;Minakaki, Georgia;Wend, Holger;Hampl, Martin;Leone, Marina;Brueckner, Martina;Klucken, Jochen;Reis, Andre;Boyer, Leah;Schuierer, Gerhard;Behrens, Juergen;Lampert, Angelika;Engel, Felix B.;Gage, Fred H.;Winkler, Juergen;Winner, Beate
编码spatacsin的痉挛性截瘫基因11（SPG 11）的突变导致最常见的常染色体隐性遗传性复杂遗传性痉挛性截瘫（HSP）和青少年型肌萎缩性侧索硬化症（ALS 5）。当SPG 11发生突变时，患者经常出现痉挛性下肢轻瘫、胼胝体变薄和认知障碍。我们先前描述了这些患者神经元的神经退行性表型。在当前的研究中，我们概述了SPG 11的早期发育表型，并概述了其在患者特异性诱导多能干细胞（iPSC）衍生的皮质神经祖细胞（NPC）中的细胞和分子机制。我们从3名SPG 11患者和2名年龄匹配的对照中产生并表征了iPSC衍生的NPC和神经元。SPG 11-NPC的基因表达谱分析揭示了神经发育途径中广泛的转录改变。这些包括细胞周期、神经发生、皮质发育途径的变化以及自噬缺陷。更重要的是，发现GSK 3 β-信号通路在SPG 11-NPC中失调。SPG 11-NPC的增殖受损导致神经细胞数量显著减少。有丝分裂活性SPG 11-NPC的减少被GSK 3调节所挽救。这种iPSC衍生的NPC模型为SPG 11中的早期神经发育表型提供了第一个证据，GSK 3 β是逆转疾病表型的潜在新靶点。《神经病学年鉴》2016;79：826-840
Mutations in the spastic paraplegia gene 11 (SPG11), encoding spatacsin, cause the most frequent form of autosomal‐recessive complex hereditary spastic paraplegia (HSP) and juvenile‐onset amyotrophic lateral sclerosis (ALS5). When SPG11 is mutated, patients frequently present with spastic paraparesis, a thin corpus callosum, and cognitive impairment. We previously delineated a neurodegenerative phenotype in neurons of these patients. In the current study, we recapitulated early developmental phenotypes of SPG11 and outlined their cellular and molecular mechanisms in patient‐specific induced pluripotent stem cell (iPSC)‐derived cortical neural progenitor cells (NPCs). We generated and characterized iPSC‐derived NPCs and neurons from 3 SPG11 patients and 2 age‐matched controls. Gene expression profiling of SPG11‐NPCs revealed widespread transcriptional alterations in neurodevelopmental pathways. These include changes in cell‐cycle, neurogenesis, cortical development pathways, in addition to autophagic deficits. More important, the GSK3ß‐signaling pathway was found to be dysregulated in SPG11‐NPCs. Impaired proliferation of SPG11‐NPCs resulted in a significant diminution in the number of neural cells. The decrease in mitotically active SPG11‐NPCs was rescued by GSK3 modulation. This iPSC‐derived NPC model provides the first evidence for an early neurodevelopmental phenotype in SPG11, with GSK3ß as a potential novel target to reverse the disease phenotype. Ann Neurol 2016;79:826–840
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DOI：
10.1093/brain/awp325
发表时间：
2010-02
期刊：
Brain : a journal of neurology
影响因子：
--
作者：
Orlacchio A;Babalini C;Borreca A;Patrono C;Massa R;Basaran S;Munhoz RP;Rogaeva EA;St George-Hyslop PH;Bernardi G;Kawarai T
通讯作者：
Kawarai T
阿尔茨海默氏病的GSK3假设。
影响因子：
4.7
作者：
Hooper C;Killick R;Lovestone S
通讯作者：
Lovestone S
影响因子：
5.8
作者：
Ahmed, A;Smoot, D;Ashktorab, H
通讯作者：
Ashktorab, H
DOI：
10.1523/jneurosci.5122-09.2010
发表时间：
2010-08-18
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Luders E;Thompson PM;Toga AW
通讯作者：
Toga AW
影响因子：
4.1
作者：
Kaproth-Joslin, Katherine A.;Li, Xiangquan;Kelley, Grant G.
通讯作者：
Kelley, Grant G.