Modeling Axonal Defects in Hereditary Spastic Paraplegia with Human Pluripotent Stem Cells.
Modeling Axonal Defects in Hereditary Spastic Paraplegia with Human Pluripotent Stem Cells.
复制标题
用人类多能干细胞模拟遗传性痉挛性截瘫的轴突缺陷。
DOI：
10.1007/s11515-016-1416-0
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发表时间：
2016
期刊：
影响因子：
--
通讯作者：
Li,Xue-Jun
中科院分区：
文献类型：
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作者：
Denton,KyleR;Xu,Chongchong;Shah,Harsh;Li,Xue-Jun
研究背景皮层运动神经元又称上运动神经元，是一种大的投射神经元，其轴突将信号传递给下运动神经元以控制肌肉运动。皮质运动神经元轴突的变性与包括遗传性痉挛性截瘫（HSP）在内的几种衰弱性疾病有关。自从第一个编码痉挛蛋白的HSP基因SPAST被发现以来，已经鉴定出70多个与HSP相关的不同基因位点。这些功能多样的基因突变如何导致轴突变性，以及为什么某些轴突在HSP中受到影响仍然是未知的。诱导多能干细胞（iPSC）技术的发展为研究人员提供了一个很好的资源，以产生患者特异性的人类神经元模型人类神经病理过程，包括轴突defects.MethodsIn这篇文章中，我们将首先审查的病理和途径，通过搜索PubMed数据库中的常见形式的HSP亚型的影响。然后，我们将总结的研究结果和见解，使用iPSC为基础的模型，并讨论挑战和未来的方向。ResultsHSPs，一组异质性遗传神经退行性疾病，表现出类似的病理变化，导致皮质运动神经元的逆行轴突变性。最近，iPSC已经从几种常见形式的HSP产生，包括SPG 4，SPG 3A和SPG 11患者。来源于HSP iPSCs的神经元表现出受损的神经突生长，增加轴突sweetness，减少轴突运输，recapitulating疾病特异性轴突defects.ConclusionsThese patient-derived neurons提供了一个独特的工具，研究致病机制，并探索拯救HSP轴突缺陷的治疗方法，以及其他涉及轴突病的疾病。
BackgroundCortical motor neurons, also known as upper motor neurons, are large projection neurons whose axons convey signals to lower motor neurons to control the muscle movements. Degeneration of cortical motor neuron axons is implicated in several debilitating disorders including hereditary spastic paraplegia (HSP). Since the discovery of the first HSP gene,SPASTthat encodes spastin, over 70 distinct genetic loci associated with HSP have been identified. How the mutations of these functionally diverse genes result in axonal degeneration and why certain axons are affected in HSP remain largely unknown. The development of induced pluripotent stem cell (iPSC) technology has provided researchers an excellent resource to generate patient-specific human neurons to model human neuropathological processes including axonal defects.MethodsIn this article, we will first review the pathology and pathways affected in the common forms of HSP subtypes by searching the PubMed database. We will then summarize the findings and insights gained from studies using iPSC-based models, and discuss challenges and future directions.ResultsHSPs, a heterogeneous group of genetic neurodegenerative disorders, exhibit similar pathological changes that result from retrograde axonal degeneration of cortical motor neurons. Recently, iPSCs have been generated from several common forms of HSP including SPG4, SPG3A, and SPG11 patients. Neurons derived from HSP iPSCs exhibit impaired neurite outgrowth, increased axonal swellings, and reduced axonal transport, recapitulating disease-specific axonal defects.ConclusionsThese patient-derived neurons offer a unique tool to study the pathogenic mechanisms and explore the treatments for rescuing axonal defects in HSP, as well as other diseases involving axonopathy.