淀粉样蛋白修饰物 SERF1a 通过螺旋相互作用与多聚谷氨酰胺扩展的 huntingtin-exon 1 相互作用，并加剧多聚谷氨酰胺诱导的毒性。
Amyloid modifier SERF1a interacts with polyQ-expanded huntingtin-exon 1 via helical interactions and exacerbates polyQ-induced toxicity.
机构信息
Genomics Research Center, Academia Sinica, 128, Academia Rd., Sec. 2, Nankang District, Taipei, 115, Taiwan.
Chemical Biology and Molecular Biophysics Program, Taiwan International Graduate Program, Institute of Biological Chemistry, Academia Sinica, 128, Academia Road, Sec. 2. Nankang, Taipei, 115, Taiwan.
出版信息
Commun Biol. 2023 Jul 21;6(1):767. doi: 10.1038/s42003-023-05142-0.
Abnormal polyglutamine (polyQ) expansion and fibrillization occur in Huntington's disease (HD). Amyloid modifier SERF enhances amyloid formation, but the underlying mechanism is not revealed. Here, the fibrillization and toxicity effect of SERF1a on Htt-exon1 are examined. SERF1a enhances the fibrillization of and interacts with mutant thioredoxin (Trx)-fused Httex1. NMR studies with Htt peptides show that TrxHttex1-39Q interacts with the helical regions in SERF1a and SERF1a preferentially interacts with the N-terminal 17 residues of Htt. Time-course analysis shows that SERF1a induces mutant TrxHttex1 to a single conformation enriched of β-sheet. Co-expression of SERF1a and Httex1-polyQ in neuroblastoma and lentiviral infection of SERF1a in HD-induced polypotent stem cell (iPSC)-derived neurons demonstrates the detrimental effect of SERF1a in HD. Higher level of SERF1a transcript or protein is detected in HD iPSC, transgenic mice, and HD plasma. Overall, this study provides molecular mechanism for SERF1a and mutant Httex1 to facilitate therapeutic development for HD.
亨廷顿病（HD）中存在异常的多聚谷氨酰胺（polyQ）扩展和纤维化。淀粉样蛋白修饰物 SERF 增强淀粉样蛋白的形成，但潜在的机制尚未揭示。本研究考察了 SERF1a 对 Htt-exon1 的纤维化和毒性作用。SERF1a 增强了突变硫氧还蛋白（Trx）融合的 Httex1 的纤维化，并与之相互作用。与 Htt 肽的 NMR 研究表明，TrxHttex1-39Q 与 SERF1a 的螺旋区相互作用，并且 SERF1a 优先与 Htt 的 N 端 17 个残基相互作用。时程分析表明，SERF1a 诱导突变的 TrxHttex1 形成富含β-折叠的单一构象。在神经母细胞瘤中共同表达 SERF1a 和 Httex1-polyQ 以及在 HD 诱导的多能干细胞（iPSC）衍生神经元中慢病毒感染 SERF1a 表明 SERF1a 在 HD 中具有有害作用。在 HD iPSC、转基因小鼠和 HD 血浆中检测到更高水平的 SERF1a 转录本或蛋白。总的来说，这项研究为 SERF1a 和突变的 Httex1 提供了分子机制，有助于开发治疗 HD 的方法。
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