Molecular pathogenesis of seipin/BSCL2-related motor neuron diseases
Molecular pathogenesis of seipin/BSCL2-related motor neuron diseases
复制标题
DOI：
10.1002/ana.21070
复制
发表时间：
2007-03-01
影响因子：
11.2
通讯作者：
Suzuki, Norihiro
中科院分区：
文献类型：
--
作者：
Ito, Daisuke;Suzuki, Norihiro
目的：最近在两种常染色体显性运动神经元疾病，远端遗传性运动神经病V型和银综合征中发现了Seipin/BSCL 2基因的杂合突变。据报道Seipin蛋白是位于内质网（ER）中的跨膜蛋白。该蛋白的N88 S和S90 L突变破坏其糖基化，导致其聚集，但神经变性的机制仍不清楚。为了阐明seipin相关的运动神经元疾病的分子发病机制，我们表达了野生型和突变体seipin蛋白在神经元和nonneuronal cells.Methods和结果：共表达的人seipin和泛素表明，seipin是聚泛素化和其泛素化是增强突变。用蛋白酶体抑制剂处理细胞增加了细胞中突变型seipin的量，表明它们通过ER相关降解途径降解。免疫沉淀研究表明，突变seipin稳定结合到ER伴侣钙连接蛋白，这表明未折叠的突变scipin在ER中的积累。此外，突变体seipin的表达增加了ER应激介导的分子的水平和诱导细胞凋亡在cultured cells.Interpretation：这些研究结果表明，seipin/BSCL 2相关的运动神经元疾病是新的构象疾病，我们怀疑，他们是紧密相关的ER应激介导的细胞死亡。
Objective: Heterozygous mutations in the Seipin/BSCL2 gene have recently been identified in two autosomal dominant motor neuron diseases, distal hereditary motor neuropathy type V and Silver's syndrome. Seipin protein is reportedly a transmembrane protein localized in the encloplasmic reticulum (ER). N88S and S90L mutations of this protein disrupt its glycosylation, resulting in its aggregation, but the mechanism of neurodegeneration remains unclear. To clarify the molecular pathogenesis of seipin-related motor neuron diseases, we expressed wild-type and mutant seipin proteins in neuronal and nonneuronal cells.Methods and Results: Coexpression of human seipin and ubiquitin showed that seipin is polyubiquitinated and its ubiquitination is enhanced by mutation. Treatment of cells with a proteasome inhibitor increased the amounts of mutant seipin in the cells, suggesting that they are degraded through the ER-associated degradation pathway. Immunoprecipitation studies showed that mutant seipin stably binds to the ER chaperone calnexin, indicating accumulation of unfolded mutant scipin in the ER. Furthermore, expression of mutant seipin increased the level of ER stress-mediated molecules and induced apoptosis in cultured cells.Interpretation: These findings demonstrate that seipin/BSCL2-related motor neuron diseases are novel conformational diseases, and we suspect that they are tightly associated with ER stress-mediated cell death.