Polymorphic SERPINA3-R124C reduces pathogenesis of its wild type by shortening the lifetime of oligomeric Aβ
Polymorphic SERPINA3-R124C reduces pathogenesis of its wild type by shortening the lifetime of oligomeric Aβ
复制标题
多态性 SERPINA3-R124C 通过缩短寡聚 Aβ 的寿命来减少其野生型的发病机制
DOI：
10.1093/bbb/zbab101
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发表时间：
2021
期刊：
影响因子：
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通讯作者：
Isobe Masaharu
中科院分区：
文献类型：
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作者：
Akbor Maruf Mohammad;Kurosawa Nobuyuki;Tanaka Masashi;Isobe Masaharu
淀粉样β（Aβ）42肽在阿尔茨海默病（AD）患者的脑中积聚，通常与丝氨酸蛋白酶抑制剂家族A成员3（SERPINA 3）共定位。SERPINA 3作为一种分子伴侣，促进Aβ42的纤维化。在分析人类SERPINA 3多态性的伴侣活性时，我们发现SERPINA 3-R124 C在保护细胞免受Aβ42细胞毒性中起作用。暴露于与野生型SERPINA 3（SERPINA 3-WT）预孵育的Aβ42的SH-SY 5 Y细胞导致延长的毒性，导致细胞死亡，而Aβ42与SERPINA 3-R124 C导致细胞毒性降低。透射电子显微镜和硫磺素T测定显示，与SERPINA 3-WT相比，SERPINA 3-R124 C缩短了小的可溶性寡聚体的寿命，并维持富含β-折叠的原纤维样聚集体更长的时间。Western blot检测证实SERPINA 3-R124 C主要将Aβ42转化为高分子聚集体。在此，我们首次证明了多态性SERPINA 3通过调节Aβ42的过渡态作为一种良性伴侣，这可能有助于降低AD的风险。
Amyloid beta (Aβ) 42 peptide accumulated in Alzheimer disease (AD) patients’ brain, often colocalized with serine protease inhibitor family A member 3 (SERPINA3). Being a chaperon, SERPINA3 accelerated Aβ42 fibrillization. While analyzing chaperon activity of human SERPINA3 polymorphisms, we found SERPINA3-R124C played a role in protecting cells from Aβ42 cytotoxicity. SH-SY5Y cells exposed to Aβ42 preincubated with wild-type SERPINA3 (SERPINA3-WT) resulted in extended toxicity leading cell death whereas Aβ42 with SERPINA3-R124C resulted in less cytotoxicity. Transmission electron microscope and thioflavin T assay revealed that SERPINA3-R124C shortened lifetime of small soluble oligomer and maintained β-sheet rich protofibril-like aggregates for longer time compared to that of with SERPINA3-WT. Western blot assay confirmed that SERPINA3-R124C converted Aβ42 mostly into high molecular aggregates. Here, we demonstrate first time that polymorphic SERPINA3 acts as a benign chaperon by modulating the transition states of Aβ42, which may contribute to the reduction of AD risk.