Survival motor neuron protein modulates neuron-specific apoptosis
Survival motor neuron protein modulates neuron-specific apoptosis
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DOI：
10.1073/pnas.230364197
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发表时间：
2000-11-21
影响因子：
11.1
通讯作者：
Hardwick, JM
中科院分区：
文献类型：
--
作者：
Kerr, DA;Nery, JP;Hardwick, JM
脊髓性肌萎缩症（SMA）是由于SMN 1基因突变导致脊髓运动神经元丢失。利用亲神经性辛德毕斯病毒载体系统研究运动神经元存活蛋白（SMN）在调节神经元凋亡中的作用。在这里，我们表明，SMN保护原代神经元和分化的神经元样干细胞，但不培养细胞系病毒诱导的凋亡。SMN还保护体内神经元，并增加病毒感染小鼠的存活率。在SMA患者中发现的SMN突变体（SMN Delta 7和SMN-Y272 C）不仅缺乏抗凋亡活性，而且具有潜在的促凋亡作用，导致神经元凋亡和动物死亡率增加。全长SMN在经历细胞凋亡或缺血性损伤后的脑中被蛋白水解加工。突变的一个天冬氨酸-252的SMN废除切割的SMM和增加的抗凋亡功能的全长SMN在神经元中。总之，由蛋白水解、剪接（SMN Δ 7）或种系突变（例如，Y272 C），产生SMN的促凋亡形式，可能导致SMA和其他神经退行性疾病中的神经元死亡。
Spinal muscular atrophy (SMA) is attributed to mutations in the SMN1 gene, leading to loss of spinal cord motor neurons. The neurotropic Sindbis virus vector system was used to investigate a role for the survival motor neuron (SMN) protein in regulating neuronal apoptosis. Here we show that SMN protects primary neurons and differentiated neuron-like stem cells, but not cultured cell lines from virus-induced apoptotic death. SMN also protects neurons in vivo and increases survival of virus-infected mice. SMN mutants (SMN Delta7 and SMN-Y272C) found in patients with SMA not only lack antiapoptotic activity but also are potently proapoptotic, causing increased neuronal apoptosis and animal mortality. Full-length SMN is proteolytically processed in brains undergoing apoptosis or after ischemic injury. Mutation of an Asp-252 of SMN abolished cleavage of SMM and increased the antiapoptotic function of full-length SMN in neurons. Taken together, deletions or mutations of the C terminus of SMN that result from proteolysis, splicing (SMN Delta7), or germ-line mutations (e.g., Y272C), produce a proapoptotic form of SMN that may contribute to neuronal death in SMA and perhaps other neurodegenerative disorders.