Golec Ewelina, Olsson Robin, Tuysuz Emre Can, Karlsson Maja, Serjieh Yasmin, King Ben C, Wennström Malin, Blom Anna M
Section of Medical Protein Chemistry, Department of Translational Medicine, Lund University, Malmö, 214-28, Sweden.
Cognitive Disorder Research Unit, Department of Clinical Sciences Malmö, Lund University, Malmö, 214-28, Sweden.
Alzheimers Res Ther. 2025 Jan 7;17(1):11. doi: 10.1186/s13195-024-01660-z.
We have previously demonstrated that the intracellular, non-GPI anchored CD59 isoforms IRIS-1 and IRIS-2 (Isoforms Rescuing Insulin Secretion 1 and 2) are necessary for insulin secretion from pancreatic β-cells. While investigating their expression across human tissues, we identified IRIS-1 and IRIS-2 mRNA in the human brain, though their protein expression and function remained unclear. This study shows the presence of both IRIS-1 and 2 proteins in the human brain, specifically in neurons and astrocytes. In the neuroblastoma cell line (SH-SY5Y), both isoforms are intracellular, and their expression increases upon differentiation into mature neurons. Silencing IRIS-1 and 2 in SH-SY5Y cells reduces the SNARE complex formation, essential for synaptic vesicle exocytosis, leading to a reduction in noradrenaline secretion. Notably, we observed diminished expression of neuronal IRIS-1 and 2 in patients with Alzheimer's disease (AD) and non-demented individuals with type 2 diabetes (T2D). In SH-SY5Y cells, knockdown of all isoforms of CD59 including IRIS-1 and 2 not only elevates phosphorylated tau but also increases cyclin-dependent kinase 5 (CDK5) expression, known promoter of hyperphosphorylation and accumulation of tau, a key pathological feature of AD. Additionally, we found that prolonged exposure to high glucose or cytokines markedly reduces the expression of IRIS-1 and 2 in SH-SY5Y cells, suggesting a link between AD pathology and metabolic stress through modulation of these isoforms.
我们之前已经证明，细胞内非糖基磷脂酰肌醇（GPI）锚定的CD59亚型IRIS-1和IRIS-2（胰岛素分泌拯救亚型1和2）对于胰腺β细胞分泌胰岛素是必需的。在研究它们在人体组织中的表达时，我们在人类大脑中鉴定出了IRIS-1和IRIS-2的信使核糖核酸（mRNA），不过它们的蛋白质表达和功能仍不清楚。这项研究表明，IRIS-1和2蛋白在人类大脑中均有存在，特别是在神经元和星形胶质细胞中。在神经母细胞瘤细胞系（SH-SY5Y）中，这两种亚型均位于细胞内，并且它们的表达在分化为成熟神经元时会增加。在SH-SY5Y细胞中沉默IRIS-1和2会减少SNARE复合体的形成，而SNARE复合体对于突触小泡胞吐作用至关重要，从而导致去甲肾上腺素分泌减少。值得注意的是，我们观察到阿尔茨海默病（AD）患者以及非痴呆的2型糖尿病（T2D）个体中神经元IRIS-1和2的表达减少。在SH-SY5Y细胞中，敲低包括IRIS-1和2在内的所有CD59亚型不仅会提高磷酸化tau水平，还会增加细胞周期蛋白依赖性激酶5（CDK5）的表达，CDK5是已知的tau过度磷酸化和积累的促进因子，而tau过度磷酸化和积累是AD的一个关键病理特征。此外，我们发现长时间暴露于高葡萄糖或细胞因子会显著降低SH-SY5Y细胞中IRIS-1和2的表达，这表明通过调节这些亚型，AD病理与代谢应激之间存在联系。
