α-Synuclein strains that cause distinct pathologies differentially inhibit proteasome

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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.

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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

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Genjiro Suzuki

Department of Dementia and Higher Brain Function, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan

For correspondence
suzuki-gj@igakuken.or.jp

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-1400-4139
Sei Imura

Department of Dementia and Higher Brain Function, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan

Competing interests
The authors declare that no competing interests exist.
Masato Hosokawa

Department of Dementia and Higher Brain Function, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan

Competing interests
The authors declare that no competing interests exist.
Ryu Katsumata

Department of Dementia and Higher Brain Function, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan

Competing interests
The authors declare that no competing interests exist.
Takashi Nonaka

Department of Dementia and Higher Brain Function, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-0830-9403
Shin-Ichi Hisanaga

Department of Biological Sciences, Tokyo Metropolitan University, Tokyo, Japan

Competing interests
The authors declare that no competing interests exist.
Yasushi Saeki

Laboratory of Protein Metabolism, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan

Competing interests
The authors declare that no competing interests exist.
Masato Hasegawa

Department of Dementia and Higher Brain Function, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan

For correspondence
hasegawa-ms@igakuken.or.jp

Competing interests
The authors declare that no competing interests exist.

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.

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) .

Copyright

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.