Department of Life Sciences and Bioengineering, Laboratory of Molecular and Cellular Biology, Faculty of Engineering, University of Toyama, Toyama, Japan.
Department of Pathophysiology, Yokohama University of Pharmacy, Yokohama, Japan.
PLoS One. 2021 Mar 4;16(3):e0248027. doi: 10.1371/journal.pone.0248027. eCollection 2021.
Molecular chaperon SERPINA3 colocalizes with accumulated amyloid peptide in Alzheimer's disease (AD) patient's brain. From the QTL analysis, we narrowed down Serpina3 with two SNPs in senescence-accelerated mouse prone (SAMP) 8 strain. Our study showed SAMP8 type Serpina3 prolonged retention of oligomeric Aβ 42 for longer duration (72 hr) while observing under transmission electron microscope (TEM). From Western blot results, we confirmed presence of Aβ 42 oligomeric forms (trimers, tetramers) were maintained for longer duration only in the presences of SAMP8 type Serpina3. Using SH-SY5Y neuroblastoma cell line, we observed until 36 hr preincubated Aβ 42 with SAMP8 type Serpina3 caused neuronal cell death compared to 12 hr preincubated Aβ 42 with SAMR1 or JF1 type Serpina3 proteins. Similar results were found by extending this study to analyze the effect of polymorphism of SERPINA3 gene of the Japanese SNP database for geriatric research (JG-SNP). We observed that polymorphic SERPINA3 I308T (rs142398813) prolonged toxic oligomeric Aβ 42 forms till 48 hr in comparison to the presence wild type SERPINA3 protein, resulting neuronal cell death. From this study, we first clarified pathogenic regulatory role of polymorphic SERPINA3 in neurodegeneration.
分子伴侣 SERPINA3 与阿尔茨海默病（AD）患者大脑中的淀粉样肽蓄积共定位。从 QTL 分析中，我们在衰老加速小鼠易感（SAMP）8 品系中发现了两个 SNP 使 Serpina3 变窄。我们的研究表明，SAMP8 型 Serpina3 延长了寡聚 Aβ 42 的保留时间（72 小时），同时在透射电子显微镜（TEM）下观察。从 Western blot 结果中，我们证实只有在存在 SAMP8 型 Serpina3 的情况下，才能更长时间地维持 Aβ 42 寡聚形式（三聚体、四聚体）。使用 SH-SY5Y 神经母细胞瘤细胞系，我们观察到在与 SAMP8 型 Serpina3 预孵育 36 小时后，与 12 小时预孵育 SAMR1 或 JF1 型 Serpina3 蛋白相比，Aβ 42 引起神经元细胞死亡。通过将这项研究扩展到分析日本老年研究 SNP 数据库（JG-SNP）中 SERPINA3 基因的多态性对其的影响，我们发现了类似的结果。我们观察到多态性 SERPINA3 I308T（rs142398813）与野生型 SERPINA3 蛋白相比，延长了有毒的寡聚 Aβ 42 形式至 48 小时，导致神经元细胞死亡。从这项研究中，我们首次阐明了多态性 SERPINA3 在神经退行性变中的致病调节作用。
