2025-04-11 中国科学院(CAS)
<関連情報>
- https://english.cas.cn/newsroom/research_news/chem/202504/t20250409_1040866.shtml
- https://www.cell.com/neuron/abstract/S0896-6273(25)00219-3
線維性ファジーコートはαシヌクレインの病理伝達活性に重要である Fibril fuzzy coat is important for α-synuclein pathological transmission activity
Yuliang Han∙ Juan Li∙ Wencheng Xia∙ … ∙ Cong Liu∙ ShengQi Xiang∙ Zhuohao He
Neuron Published:April 10, 2025
DOI:https://doi.org/10.1016/j.neuron.2025.03.019
Graphical abstract
Highlights
- Pathological α-synuclein fibrils with similar core regions exhibit polymorphisms
- The flexibility of the fuzzy coat regulates α-synuclein pathological transmission
- α-synuclein polymorphisms are present within the same human disease brain
Summary
α-synuclein transmission and propagation are hallmarks of synucleinopathies, yet the molecular mechanisms remain elusive. Using α-synuclein preformed fibrils as pathological seeds, we observed a gradual decline in neuronal transmission activity during serial propagation. Fibril polymorphisms were identified from the initial generation: mini-P, with higher neuronal seeding activity, and mini-S, which accelerated recombinant α-synuclein aggregation. Changes in their proportions during propagation explained the overall decline in transmission activity. Cryoelectron microscopy and solid-state nuclear magnetic resonance revealed that both fibrils shared similar core regions but differed in their fuzzy coat flexibilities. The interaction between the fuzzy coat and fibril core substantially influenced neuronal transmission, a model further supported by hydrogen/deuterium exchange mass spectrometry. A mini-P-selective antibody identified active fibril types in newly propagated brain regions in human synucleinopathies. This study highlights the fuzzy coat’s pivotal role in pathological protein transmission and suggests it as a potential therapeutic target for synucleinopathies.
