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.

Metrics

  • 3,000
    Page views
  • 642
    Downloads
  • 24
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, Scopus, PubMed Central.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  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
  1. Further reading

Further reading

    1. Neuroscience
    Andrew P Davison, Shailesh Appukuttan
    Insight

    Artificial neural networks could pave the way for efficiently simulating large-scale models of neuronal networks in the nervous system.

    1. Neuroscience
    Jonathan Nicholas, Nathaniel D Daw, Daphna Shohamy
    Research Article

    A key question in decision making is how humans arbitrate between competing learning and memory systems to maximize reward. We address this question by probing the balance between the effects, on choice, of incremental trial-and-error learning versus episodic memories of individual events. Although a rich literature has studied incremental learning in isolation, the role of episodic memory in decision making has only recently drawn focus, and little research disentangles their separate contributions. We hypothesized that the brain arbitrates rationally between these two systems, relying on each in circumstances to which it is most suited, as indicated by uncertainty. We tested this hypothesis by directly contrasting contributions of episodic and incremental influence to decisions, while manipulating the relative uncertainty of incremental learning using a well-established manipulation of reward volatility. Across two large, independent samples of young adults, participants traded these influences off rationally, depending more on episodic information when incremental summaries were more uncertain. These results support the proposal that the brain optimizes the balance between different forms of learning and memory according to their relative uncertainties and elucidate the circumstances under which episodic memory informs decisions.