α-Synuclein strains that cause distinct pathologies differentially inhibit proteasome
- Tokyo Metropolitan Institute of Medical Science, Japan
- Tokyo Metropolitan University, Japan
Abstract
Abnormal α-synuclein aggregation has been implicated in several diseases and is known to spread in a prion-like manner. There is a relationship between protein aggregate structure (strain) and clinical phenotype in prion diseases, however, whether differences in the strains of α‑synuclein aggregates account for the different pathologies remained unclear. Here, we generated two types of α-synuclein fibrils from identical monomer and investigated their seeding and propagation ability in mice and primary-cultured neurons. One α-synuclein fibril induced marked accumulation of phosphorylated α-synuclein and ubiquitinated protein aggregates, while the other did not, indicating the formation of α-synuclein two strains. Notably, the former α‑synuclein strain inhibited proteasome activity and co-precipitated with 26S proteasome complex. Further examination indicated that structural differences in the C-terminal region of α‑synuclein strains lead to different effects on proteasome activity. These results provide a possible molecular mechanism to account for the different pathologies induced by different α‑synuclein strains.
Data availability
All data generated or analysed during this study are included in the manuscript and supporting files. Source data files have been provided for Figures 1, 3, 4 and 5.
Article and author information
Author details
Funding
Japan Society for the Promotion of Science (16K21650)
- Genjiro Suzuki
Ichiro Kanehara Foundation for the Promotion of Medical Sciences and Medical Care
- Genjiro Suzuki
Kato Memorial Bioscience Foundation
- Genjiro Suzuki
Ministry of Education, Culture, Sports, Science, and Technology (26117005)
- Masato Hasegawa
Core Research for Evolutional Science and Technology (JPMJCR18H3)
- Masato Hasegawa
Japan Agency for Medical Research and Development (JP18dm0207019)
- Masato Hasegawa
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Hitoshi Nakatogawa, Tokyo Institute of Technology, Japan
Ethics
Animal experimentation: All experimental protocols were performed according to the recommendations of the Animal Care and Use Committee of Tokyo Metropolitan Institute of Medical Science (#18040, #19042, #20-035) .
Version history
- Received: March 11, 2020
- Accepted: July 22, 2020
- Accepted Manuscript published: July 22, 2020 (version 1)
- Version of Record published: August 5, 2020 (version 2)
Copyright
© 2020, Suzuki et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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α-Synuclein strains that cause distinct pathologies differentially inhibit proteasome
eLife 9:e56825.
https://doi.org/10.7554/eLife.56825
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