α-Synuclein strains that cause distinct pathologies differentially inhibit proteasome

  1. Genjiro Suzuki  Is a corresponding author
  2. Sei Imura
  3. Masato Hosokawa
  4. Ryu Katsumata
  5. Takashi Nonaka
  6. Shin-Ichi Hisanaga
  7. Yasushi Saeki
  8. Masato Hasegawa  Is a corresponding author
  1. Tokyo Metropolitan Institute of Medical Science, Japan
  2. 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

  1. 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.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1400-4139
  2. 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.
  3. 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.
  4. 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.
  5. 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.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0830-9403
  6. Shin-Ichi Hisanaga

    Department of Biological Sciences, Tokyo Metropolitan University, Tokyo, Japan
    Competing interests
    The authors declare that no competing interests exist.
  7. Yasushi Saeki

    Laboratory of Protein Metabolism, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan
    Competing interests
    The authors declare that no competing interests exist.
  8. 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) .

Reviewing Editor

  1. Hitoshi Nakatogawa, Tokyo Institute of Technology, Japan

Publication history

  1. Received: March 11, 2020
  2. Accepted: July 22, 2020
  3. Accepted Manuscript published: July 22, 2020 (version 1)
  4. 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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  1. Genjiro Suzuki
  2. Sei Imura
  3. Masato Hosokawa
  4. Ryu Katsumata
  5. Takashi Nonaka
  6. Shin-Ichi Hisanaga
  7. Yasushi Saeki
  8. Masato Hasegawa
(2020)
α-Synuclein strains that cause distinct pathologies differentially inhibit proteasome
eLife 9:e56825.
https://doi.org/10.7554/eLife.56825

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