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register hereHeterozygous loss-of-function mutations in the GRN gene are a common cause of frontotemporal dementia. Such mutations lead to decreased plasma and cerebrospinal fluid levels of progranulin (PGRN), a neurotrophic factor with lysosomal functions. Sortilin is a negative regulator of extracellular PGRN levels and has shown promise as a therapeutic target for frontotemporal dementia, enabling increased extracellular PGRN levels through inhibition of sortilin-mediated PGRN degradation.

在此登记GRN基因中的杂合功能丧失突变是额颞叶痴呆的常见原因。这种突变导致血浆和脑脊液中颗粒蛋白原（PGRN）水平降低，颗粒蛋白原是一种具有溶酶体功能的神经营养因子。分拣蛋白是细胞外PGRN水平的负调节剂，并且已经显示出作为额颞叶痴呆的治疗靶标的前景，通过抑制分拣蛋白介导的PGRN降解来增加细胞外PGRN水平。

Here we report the development of a high-affinity sortilin-binding affibody-peptide fusion construct capable of increasing extracellular PGRN levels in vitro. By genetic fusion of a sortilin-binding affibody generated through phage display and a peptide derived from the progranulin C-terminus, an affinity protein (A3-PGRNC15*) with 185-pM affinity for sortilin was obtained.

在这里，我们报告了能够在体外增加细胞外PGRN水平的高亲和力分拣蛋白结合affibody肽融合构建体的开发。通过噬菌体展示产生的分拣蛋白结合抗体与源自颗粒蛋白前体C末端的肽的遗传融合，获得了对分拣蛋白具有185 pM亲和力的亲和蛋白（A3-PGRNC15*）。

Treating PGRN-secreting and sortilin-expressing human glioblastoma U-251 cells with the fusion protein increased extracellular PGRN levels up to 2.5-fold, with an EC50 value of 1.3 nM. Our results introduce A3-PGRNC15* as a promising new agent with therapeutic potential for the treatment of frontotemporal dementia.

用融合蛋白处理分泌PGRN和表达分拣蛋白的人胶质母细胞瘤U-251细胞可使细胞外PGRN水平提高2.5倍，EC50值为1.3 nM。我们的研究结果介绍了A3-PGRNC15*作为一种有前途的新药，具有治疗额颞叶痴呆的治疗潜力。

Furthermore, the work highlights means to increase binding affinity through synergistic contribution from two orthogonal polypeptide units..

此外，这项工作强调了通过两个正交多肽单元的协同贡献来提高结合亲和力的方法。。