Umeå Centre for Molecular Medicine, Umeå University, 901 87, Umeå, Sweden.
Department of Chemistry, Umeå University, 901 87, Umeå, Sweden.
Sci Rep. 2020 Nov 24;10(1):20438. doi: 10.1038/s41598-020-77409-z.
Type 2 diabetes (T2D), alike Parkinson's disease (PD), belongs to the group of protein misfolding diseases (PMDs), which share aggregation of misfolded proteins as a hallmark. Although the major aggregating peptide in β-cells of T2D patients is Islet Amyloid Polypeptide (IAPP), alpha-synuclein (αSyn), the aggregating peptide in substantia nigra neurons of PD patients, is expressed also in β-cells. Here we show that αSyn, encoded by Snca, is a component of amyloid extracted from pancreas of transgenic mice overexpressing human IAPP (denoted hIAPPtg mice) and from islets of T2D individuals. Notably, αSyn dose-dependently promoted IAPP fibril formation in vitro and tail-vein injection of αSyn in hIAPPtg mice enhanced β-cell amyloid formation in vivo whereas β-cell amyloid formation was reduced in hIAPPtg mice on a Snca background. Taken together, our findings provide evidence that αSyn and IAPP co-aggregate both in vitro and in vivo, suggesting a role for αSyn in β-cell amyloid formation.
2 型糖尿病（T2D）与帕金森病（PD）一样，属于蛋白质错误折叠疾病（PMDs）组，其特征是错误折叠的蛋白质聚集。尽管 T2D 患者β细胞中的主要聚集肽是胰岛淀粉样多肽（IAPP），但 PD 患者黑质神经元中的聚集肽α-突触核蛋白（αSyn）也在β细胞中表达。在这里，我们表明αSyn，由 Snca 编码，是从过度表达人 IAPP（表示为 hIAPPtg 小鼠）的转基因小鼠胰腺中提取的淀粉样蛋白和 T2D 个体胰岛中的淀粉样蛋白的组成部分。值得注意的是，αSyn 以剂量依赖的方式促进体外 IAPP 纤维形成，并且αSyn 的尾静脉注射在 hIAPPtg 小鼠中增强了体内β细胞淀粉样形成，而在 Snca 背景下的 hIAPPtg 小鼠中β细胞淀粉样形成减少。总之，我们的研究结果提供了证据表明αSyn 和 IAPP 在体外和体内共同聚集，表明αSyn 在β细胞淀粉样形成中的作用。
