N88S seipin mutant transgenic mice develop features of seipinopathy/BSCL2-related motor neuron disease via endoplasmic reticulum stress
N88S seipin mutant transgenic mice develop features of seipinopathy/BSCL2-related motor neuron disease via endoplasmic reticulum stress
复制标题
DOI：
10.1093/hmg/ddr304
复制
发表时间：
2011-10-01
影响因子：
3.5
通讯作者：
Suzuki, Norihiro
中科院分区：
文献类型：
--
作者：
Yagi, Takuya;Ito, Daisuke;Suzuki, Norihiro
seipin/BSCL2 N-糖基化位点突变（N88S 和 P90L）的杂合性与常染色体显性运动神经元疾病、痉挛性截瘫 17 和 V 型远端遗传性运动神经病（称为“seipino 病”）相关。先前的体外研究表明，与丝氨酸病相关的突变导致未折叠蛋白在内质网（ER）中积累，从而导致未折叠蛋白反应和细胞死亡，这表明丝氨酸病与内质网应激密切相关。为了进一步了解 seipin 病的分子发病机制，我们构建了表达人类 N88S seipin 突变体和鼠 Thy-1 启动子的转基因 (tg) 小鼠系，以允许分析体内表型变化。 N88S seipin tg 小鼠出现进行性痉挛性运动缺陷、脊髓反应性神经胶质增生和神经源性肌肉萎缩，概括了 seipin 病患者的症状和病理表型。我们还发现，小鼠中突变型seipin的表达上调了内质网应激标记物、免疫球蛋白重链结合蛋白、蛋白质二硫键异构酶和X-box结合蛋白1，但与受影响组织中的显着神经元损失无关，因此表明内质网应激对于seipin病运动表型的发展来说是足够的，而神经元死亡并不是必需的。我们在突变型 seipin tg 小鼠中的发现为理解 ER 应激和神经变性之间的关系提供了线索，并且 seipin tg 小鼠是开发针对 ER 应激相关疾病的新型治疗策略的有效工具。
Heterozygosity for mutations (N88S and P90L) in the N-glycosylation site of seipin/BSCL2 is associated with the autosomal dominant motor neuron diseases, spastic paraplegia 17 and distal hereditary motor neuropathy type V, referred to as 'seipinopathies'. Previous in vitro studies have shown that seipinopathy-linked mutations result in accumulation of unfolded proteins in the endoplasmic reticulum (ER), leading to the unfolded protein response and cell death, suggesting that seipinopathies is closely associated with ER stress. To further understand the molecular pathogenesis of seipinopathies, we generated a transgenic (tg) mouse line expressing the human N88S seipin mutant with the murine Thy-1 promoter to permit analyses of in vivo phenotypic changes. The N88S seipin tg mice develop a progressive spastic motor deficit, reactive gliosis in the spinal cord and neurogenic muscular atrophy, recapitulating the symptomatic and pathological phenotype in patients of seipinopathy. We also found that expression of mutant seipin in mice upregulated the ER stress marker, immunoglobulin-heavy-chain-binding protein, protein disulfide isomerase and X-box binding protein 1, but was not linked to significant neuronal loss in affected tissue, thereby indicating that ER stress is sufficient, while neuronal death is not necessary, for the development of motor phenotypes of seipinopathies. Our findings in the mutant seipin tg mouse provide clues to understand the relationship with ER stress and neurodegeneration, and the seipin tg mouse is a valid tool for the development of novel therapeutic strategies against ER stress-related diseases.