A patient-derived stem cell model of hereditary spastic paraplegia with SPAST mutations.
A patient-derived stem cell model of hereditary spastic paraplegia with SPAST mutations.
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DOI：
10.1242/dmm.010884
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发表时间：
2013-03
影响因子：
4.3
通讯作者：
Mackay-Sim A
中科院分区：
文献类型：
--
作者：
Abrahamsen G;Fan Y;Matigian N;Wali G;Bellette B;Sutharsan R;Raju J;Wood SA;Veivers D;Sue CM;Mackay-Sim A
遗传性痉挛性截瘫（HSP）导致进行性步态障碍与下肢肌肉无力和痉挛。SPAST突变是成人发病的常染色体显性HSP的主要原因。SPAST编码的蛋白Spastin是一种微管切断蛋白，富集于HSP患者退行性皮质脊髓运动神经元的远端轴突。动物和细胞模型已经确定了spastin和突变spastin的功能，但这些模型缺乏表征该疾病患者的基因剂量、突变变异性和遗传背景。在本研究中，通过比较从健康对照者的嗅粘膜活检中提取的神经祖细胞与来自SPAST突变的HSP患者的类似细胞，来确定HSP中细胞功能的改变，从而包含了这种遗传变异性。患者来源的细胞在增殖和多种代谢功能方面与对照来源的细胞相似，但存在主要的基因表达失调，57%的mRNA转录受到影响，包括许多与微管动力学相关的转录。与对照细胞相比，患者来源的细胞含有50%的痉挛蛋白、50%的乙酰化α-微管蛋白和150%的安定素（一种微管不稳定酶）。患者来源的细胞比对照细胞小。它们改变了细胞内过氧化物酶体和线粒体的分布，并且过氧化物酶体的移动速度较慢。这些结果表明，患者来源的细胞可能补偿了痉挛素的减少，但其增加的镇静素表达减少了稳定的微管和改变的细胞器运输。微管结合药物紫杉醇和vinblastine的亚纳摩尔浓度可增加患者细胞中乙酰化α-微管蛋白的水平，从而控制其水平，表明该细胞模型可用于筛选其他药物治疗候选化合物。
Hereditary spastic paraplegia (HSP) leads to progressive gait disturbances with lower limb muscle weakness and spasticity. Mutations in SPAST are a major cause of adult-onset, autosomal-dominant HSP. Spastin, the protein encoded by SPAST, is a microtubule-severing protein that is enriched in the distal axon of corticospinal motor neurons, which degenerate in HSP patients. Animal and cell models have identified functions of spastin and mutated spastin but these models lack the gene dosage, mutation variability and genetic background that characterize patients with the disease. In this study, this genetic variability is encompassed by comparing neural progenitor cells derived from biopsies of the olfactory mucosa from healthy controls with similar cells from HSP patients with SPAST mutations, in order to identify cell functions altered in HSP. Patient-derived cells were similar to control-derived cells in proliferation and multiple metabolic functions but had major dysregulation of gene expression, with 57% of all mRNA transcripts affected, including many associated with microtubule dynamics. Compared to control cells, patient-derived cells had 50% spastin, 50% acetylated α-tubulin and 150% stathmin, a microtubule-destabilizing enzyme. Patient-derived cells were smaller than control cells. They had altered intracellular distributions of peroxisomes and mitochondria and they had slower moving peroxisomes. These results suggest that patient-derived cells might compensate for reduced spastin, but their increased stathmin expression reduced stabilized microtubules and altered organelle trafficking. Sub-nanomolar concentrations of the microtubule-binding drugs, paclitaxel and vinblastine, increased acetylated α-tubulin levels in patient cells to control levels, indicating the utility of this cell model for screening other candidate compounds for drug therapies.
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影响因子：
3.7
作者：
Cook AL;Vitale AM;Ravishankar S;Matigian N;Sutherland GT;Shan J;Sutharsan R;Perry C;Silburn PA;Mellick GD;Whitelaw ML;Wells CA;Mackay-Sim A;Wood SA
通讯作者：
Wood SA
影响因子：
64.8
作者：
Hubbert, C;Guardiola, A;Yao, TP
通讯作者：
Yao, TP
影响因子：
4.8
作者：
Manna, Tapas;Thrower, Douglas A.;Wilson, Leslie
通讯作者：
Wilson, Leslie
影响因子：
4
作者：
Nguyen, T;Bjorkman, J;Crane, DI
通讯作者：
Crane, DI
影响因子：
4.5
作者：
Mar JC;Matigian NA;Mackay-Sim A;Mellick GD;Sue CM;Silburn PA;McGrath JJ;Quackenbush J;Wells CA
通讯作者：
Wells CA