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Cellular milieu imparts distinct pathological α-synuclein strains in α-synucleinopathies

Author

Listed:
  • Chao Peng

    (the Perelman School of Medicine at the University of Pennsylvania)

  • Ronald J. Gathagan

    (the Perelman School of Medicine at the University of Pennsylvania)

  • Dustin J. Covell

    (the Perelman School of Medicine at the University of Pennsylvania)

  • Coraima Medellin

    (the Perelman School of Medicine at the University of Pennsylvania)

  • Anna Stieber

    (the Perelman School of Medicine at the University of Pennsylvania)

  • John L. Robinson

    (the Perelman School of Medicine at the University of Pennsylvania)

  • Bin Zhang

    (the Perelman School of Medicine at the University of Pennsylvania)

  • Rose M. Pitkin

    (the Perelman School of Medicine at the University of Pennsylvania)

  • Modupe F. Olufemi

    (the Perelman School of Medicine at the University of Pennsylvania)

  • Kelvin C. Luk

    (the Perelman School of Medicine at the University of Pennsylvania)

  • John Q. Trojanowski

    (the Perelman School of Medicine at the University of Pennsylvania)

  • Virginia M.-Y. Lee

    (the Perelman School of Medicine at the University of Pennsylvania)

Abstract

In Lewy body diseases—including Parkinson’s disease, without or with dementia, dementia with Lewy bodies, and Alzheimer’s disease with Lewy body co-pathology 1 —α-synuclein (α-Syn) aggregates in neurons as Lewy bodies and Lewy neurites 2 . By contrast, in multiple system atrophy α-Syn accumulates mainly in oligodendrocytes as glial cytoplasmic inclusions (GCIs) 3 . Here we report that pathological α-Syn in GCIs and Lewy bodies (GCI-α-Syn and LB-α-Syn, respectively) is conformationally and biologically distinct. GCI-α-Syn forms structures that are more compact and it is about 1,000-fold more potent than LB-α-Syn in seeding α-Syn aggregation, consistent with the highly aggressive nature of multiple system atrophy. GCI-α-Syn and LB-α-Syn show no cell-type preference in seeding α-Syn pathology, which raises the question of why they demonstrate different cell-type distributions in Lewy body disease versus multiple system atrophy. We found that oligodendrocytes but not neurons transform misfolded α-Syn into a GCI-like strain, highlighting the fact that distinct α-Syn strains are generated by different intracellular milieus. Moreover, GCI-α-Syn maintains its high seeding activity when propagated in neurons. Thus, α-Syn strains are determined by both misfolded seeds and intracellular environments.

Suggested Citation

  • Chao Peng & Ronald J. Gathagan & Dustin J. Covell & Coraima Medellin & Anna Stieber & John L. Robinson & Bin Zhang & Rose M. Pitkin & Modupe F. Olufemi & Kelvin C. Luk & John Q. Trojanowski & Virginia, 2018. "Cellular milieu imparts distinct pathological α-synuclein strains in α-synucleinopathies," Nature, Nature, vol. 557(7706), pages 558-563, May.
  • Handle: RePEc:nat:nature:v:557:y:2018:i:7706:d:10.1038_s41586-018-0104-4
    DOI: 10.1038/s41586-018-0104-4
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    Cited by:

    1. Martin Wilkinson & Rodrigo U. Gallardo & Roberto Maya Martinez & Nicolas Guthertz & Masatomo So & Liam D. Aubrey & Sheena E. Radford & Neil A. Ranson, 2023. "Disease-relevant β2-microglobulin variants share a common amyloid fold," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    2. Jinjian Hu & Wencheng Xia & Shuyi Zeng & Yeh-Jun Lim & Youqi Tao & Yunpeng Sun & Lang Zhao & Haosen Wang & Weidong Le & Dan Li & Shengnan Zhang & Cong Liu & Yan-Mei Li, 2024. "Phosphorylation and O-GlcNAcylation at the same α-synuclein site generate distinct fibril structures," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    3. Youqi Tao & Yunpeng Sun & Shiran Lv & Wencheng Xia & Kun Zhao & Qianhui Xu & Qinyue Zhao & Lin He & Weidong Le & Yong Wang & Cong Liu & Dan Li, 2022. "Heparin induces α-synuclein to form new fibril polymorphs with attenuated neuropathology," Nature Communications, Nature, vol. 13(1), pages 1-9, December.
    4. Norihito Uemura & Nicholas P. Marotta & Jahan Ara & Emily S. Meymand & Bin Zhang & Hiroshi Kameda & Masato Koike & Kelvin C. Luk & John Q. Trojanowski & Virginia M.-Y. Lee, 2023. "α-Synuclein aggregates amplified from patient-derived Lewy bodies recapitulate Lewy body diseases in mice," Nature Communications, Nature, vol. 14(1), pages 1-17, December.

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