Conformational Switch in the Alpha‐Synuclein C‐Terminal Domain Directs Its Fibril Polymorphs
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.
Authors
- Yoh Matsuki (ORCID: https://orcid.org/0000-0001-5339-6123)
- Masatomo So (ORCID: https://orcid.org/0000-0002-4815-4995)
- Yuji Goto (ORCID: https://orcid.org/0000-0003-1221-1270)
- Susumu Uchiyama (ORCID: https://orcid.org/0000-0002-5181-179X)
- Yu Yamamori (ORCID: https://orcid.org/0000-0003-2854-212X)
- Hiroko Inoura (ORCID: https://orcid.org/0000-0003-4345-8348)
- Hideki Mochizuki (ORCID: https://orcid.org/0000-0002-0874-7542)
- Yasuyoshi Kimura (ORCID: https://orcid.org/0000-0001-9147-8058)
- Keita Kakuda (ORCID: https://orcid.org/0000-0003-2563-5443)
- Chi‐Jing Choong (ORCID: https://orcid.org/0000-0001-7605-7618)
- Takahiro Maruno (ORCID: https://orcid.org/0000-0003-1099-2536)
- Yohei Miyanoiri (ORCID: https://orcid.org/0000-0001-6889-5160)
- Seiichi Nagano (ORCID: https://orcid.org/0000-0002-0826-177X)
- Kichitaro Nakajima (ORCID: https://orcid.org/0000-0003-2644-741X)
- Tatsuhiko Ozono (ORCID: https://orcid.org/0000-0002-0439-6183)
- Kentaro Tomii (ORCID: https://orcid.org/0000-0002-4567-4768)
- Kensuke Ikenaka (ORCID: https://orcid.org/0000-0002-5559-1966)
- Kousuke Baba
- Yoshitaka Nagai (ORCID: https://orcid.org/0000-0003-1037-3129)
- Takahiro Ajiki
- Junko Doi
- Nan Wang (ORCID: https://orcid.org/0000-0002-5920-9314)
- Keiichi Yamaguchi
- H Tamaki (ORCID: https://orcid.org/0009-0000-5674-2706)
- Hirotsugu Ogi (ORCID: https://orcid.org/0000-0001-9684-4715)
- César Aguirre
Institutions
- Kyoto University (JP)
- Kindai University Hospital (JP)
- Museum of Japanese Art Yamato Bunkakan (JP)
- Protein Research Foundation (JP)
- National Institute of Advanced Industrial Science and Technology (JP)
- Kindai University (JP)
- The University of Osaka (JP)
Publication Details
- Journal
- Chemistry - A European Journal
- Published
- 2025-05-23
- DOI
- https://doi.org/10.1002/chem.202500650
- Citations
- 3
- Primary Topic
- Parkinson's Disease Mechanisms and Treatments
- Type
- article
- Field-Weighted Citation Impact
- 4.17
Funders
- Japan Agency for Medical Research and Development
- Japan Society for the Promotion of Science