Mutations of SPG4 are responsible for a loss of function of spastin, an abundant neuronal protein localized in the nucleus
Mutations of SPG4 are responsible for a loss of function of spastin, an abundant neuronal protein localized in the nucleus
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DOI：
10.1093/hmg/ddg004
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发表时间：
2003-01-01
影响因子：
3.5
通讯作者：
Betuing, S
中科院分区：
文献类型：
--
作者：
Charvin, D;Cifuentes-Diaz, C;Betuing, S
痉挛蛋白的突变是最常见的常染色体显性遗传性痉挛截瘫(AD-HSP)的原因，AD-HSP是一种以皮质脊髓束和后柱轴突变性为特征的疾病。针对spastin的多克隆抗体的产生已经在人类和小鼠组织中发现了两种75 kDa和80 kDa的异构体，其异构体比率具有组织特异性的可变性。Spastin是神经组织中含量丰富的蛋白质，免疫标记实验表明，Spastin在神经元中表达，但在神经胶质细胞中不表达。这些数据表明，与痉挛蛋白突变有关的轴突退化是由神经元的初级缺陷引起的。对携带无义或移码痉挛蛋白突变的患者进行的蛋白质和转录本分析显示，既没有截断的蛋白质，也没有突变的转录本，这提供了这些突变导致痉挛蛋白功能丧失的证据。识别能够诱导非突变的spastin等位基因表达的药物应该是一种有吸引力的治疗策略。
Mutations of spastin are responsible for the most common autosomal dominant form of hereditary spastic paraplegia (AD-HSP), a disease characterized by axonal degeneration of corticospinal tracts and posterior columns. Generation of polyclonal antibodies specific to spastin has revealed two isoforms of 75 and 80 kDa in both human and mouse tissues with a tissue-specific variability of the isoform ratio. Spastin is an abundant protein in neural tissues and immunolabeling experiments have shown that spastin is expressed in neurons but not in glial cells. These data indicate that axonal degeneration linked to spastin mutations is caused by a primary defect of neurons. Protein and transcript analyses of patients carrying either nonsense or frameshift spastin mutations revealed neither truncated protein nor mutated transcripts, providing evidence that these mutations are responsible for a loss of spastin function. Identifying agents able to induce the expression of the non-mutated spastin allele should represent an attractive therapeutic strategy in this disease.