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首页> 美国卫生研究院文献>Journal of the Boston Society of Medical Sciences >S20G Mutant Amylin Exhibits Increased in Vitro Amyloidogenicity and Increased Intracellular Cytotoxicity Compared to Wild-Type Amylin
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S20G Mutant Amylin Exhibits Increased in Vitro Amyloidogenicity and Increased Intracellular Cytotoxicity Compared to Wild-Type Amylin

机译：与野生型胰岛淀粉样变性蛋白相比S20G突变体胰岛淀粉样变性蛋白具有更高的体外淀粉样变性和细胞内细胞毒性

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Human amylin, a major constituent of pancreatic amyloid deposits, may be a pathogenetic factor for noninsulin-dependent diabetes mellitus (NIDDM). We demonstrated that the human amylin S20G gene mutation (S20G) was associated with a history of early onset, more severe type of NIDDM, linking the amylin gene to this disease. Also, we demonstrated that expression of human wild-type (WT) amylin in COS-1 cells leads to intracellular amyloidogenesis and induction of apoptosis, suggesting a possible mechanism for disease induction. Therefore we compared the abilities of S20G and WT amylin to induce apoptosis in transfected COS-1 cells and form amyloid in vitro. We transfected the rat (RAT), mutated human (MUT), WT, and S20G amylin genes into COS-1 cells and measured apoptosis using fluorescent-activated cell sorting analysis at 48, 72, and 96 hours. At 96 hours apoptosis increased significantly (P < 0.01) in cells transfected with WT and S20G over RAT or MUT (WT, 19%; S20G, 25%; RAT, 13%; and MUT, 12%) and the difference between WT and S20G was significant (P < 0.05). Synthetic WT and S20G monomeric peptides were used to generate amyloid fibrils in vitro as measured by the thioflavin T binding assay. The S20G amylin formed approximately twofold more amyloid at a rate approximately threefold higher than WT. Electron micrography indicated that the in vitro amyloid generated by WT and S20G amylins were morphologically indistinguishable. The results suggest that increased cytotoxicity by S20G is because of increased amyloidogenicity, which may be a causative factor in the early development of NIDDM, possibly through loss of β cell mass.
机译：人胰岛淀粉样多肽是胰腺淀粉样蛋白沉积的主要成分，可能是非胰岛素依赖型糖尿病（NIDDM）的致病因素。我们证明了人类胰岛淀粉样多肽S20G基因突变（S20G）与早期发作，更严重的NIDDM类型的病史相关，并将胰岛淀粉样多肽基因与该疾病联系起来。此外，我们证明了在COS-1细胞中表达人类野生型（WT）胰岛淀粉样多肽可导致细胞内淀粉样蛋白生成和细胞凋亡的诱导，提示了疾病诱导的可能机制。因此，我们比较了S20G和WT淀粉酶在转染的COS-1细胞中诱导细胞凋亡并在体外形成淀粉样蛋白的能力。我们将大鼠（RAT），突变的人（MUT），WT和S20G胰岛淀粉样多肽基因转染到COS-1细胞中，并在48、72和96小时使用荧光激活的细胞分选分析测量了细胞凋亡。在96小时时，与RAT或MUT相比，WT和S20G转染的细胞凋亡显着增加（P <0.01）（WT，19％； S20G，25％； RAT，13％； MUT，12％），WT与SUT之间的差异S20G显着（P <0.05）。合成的WT和S20G单体肽用于体外产生淀粉样原纤维，如通过硫代黄素T结合测定法所测量的。 S20G胰岛淀粉样多肽形成的淀粉样蛋白多约两倍，其形成速率比野生型高约三倍。电子显微照片表明，WT和S20G淀粉样蛋白产生的体外淀粉样蛋白在形态上是无法区分的。结果表明，S20G引起的细胞毒性增加是由于淀粉样变性增加，这可能是NIDDM早期发展的病因，可能是由于β细胞量减少所致。

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