Aguirre Cesar, Miyanoiri Yohei, So Masatomo, Tamaki Hajime, Maruno Takahiro, Doi Junko, Wang Nan, Yamaguchi Keiichi, Nakajima Kichitaro, Yamamori Yu, Inoura Hiroko, Choong Chi-Jing, Kakuda Keita, Ajiki Takahiro, Kimura Yasuyoshi, Ozono Tatsuhiko, Baba Kousuke, Nagano Seiichi, Nagai Yoshitaka, Ogi Hirotsugu, Uchiyama Susumu, Matsuki Yoh, Tomii Kentaro, Goto Yuji, Ikenaka Kensuke, Mochizuki Hideki
Department of Neurology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.
Laboratory for Ultra-High Magnetic Field NMR Spectroscopy, Research Center for Next-Generation Protein Sciences, Institute for Protein Research, Osaka University, Japan, 3-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.
Chemistry. 2025 Jul 2;31(37):e202500650. doi: 10.1002/chem.202500650. Epub 2025 Jun 1.
α-Synuclein (αSyn) inclusions are a pathological hallmark of several neurodegenerative disorders. While cryo-electron microscopy studies have revealed distinct fibril polymorphs across different synucleinopathies, the molecular switches controlling polymorphism remain unveiled. In this study, we found that fibril morphology is associated with the conformational state of monomeric αSyn. Through systematic evaluation of the ionic strength and temperature, we generated two distinct polymorphs: a twisted morphology at low ionic strength and temperature, and a rod-like morphology at higher ionic strength and temperature. Using solid-state NMR, we revealed that both polymorphs share a highly conserved core structure, with morphological differences arising probably from distinct structural arrangements at the protofilament interfaces. Furthermore, we found that a specific conformational change in the C-terminal domain of the monomeric αSyn serves as a molecular switch for the formation of polymorphs. Interestingly, this conformational change can also be triggered by calcium binding to the C-terminus, connecting environmental factors to specific fibril architectures. Our results reveal a conformational role for the C-terminal domain that influences αSyn fibril morphology, providing significant insights into the fibrogenesis of αSyn.
α-突触核蛋白（αSyn）聚集体是几种神经退行性疾病的病理标志。虽然冷冻电子显微镜研究揭示了不同突触核蛋白病中不同的纤维多态性，但控制多态性的分子开关仍不明确。在本研究中，我们发现纤维形态与单体αSyn的构象状态相关。通过系统评估离子强度和温度，我们产生了两种不同的多态性：在低离子强度和温度下为扭曲形态，在较高离子强度和温度下为棒状形态。使用固态核磁共振，我们揭示这两种多态性都具有高度保守的核心结构，形态差异可能源于原纤维界面处不同的结构排列。此外，我们发现单体αSyn C末端结构域的特定构象变化作为多态性形成的分子开关。有趣的是，这种构象变化也可以由钙结合到C末端触发，将环境因素与特定的纤维结构联系起来。我们的结果揭示了C末端结构域影响αSyn纤维形态的构象作用，为αSyn的纤维化形成提供了重要见解。
