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α-Synuclein aggregates amplified from patient-derived Lewy bodies recapitulate Lewy body diseases in mice

Author

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  • Norihito Uemura

    (University of Pennsylvania School of Medicine)

  • Nicholas P. Marotta

    (University of Pennsylvania School of Medicine)

  • Jahan Ara

    (University of Pennsylvania School of Medicine)

  • Emily S. Meymand

    (University of Pennsylvania School of Medicine)

  • Bin Zhang

    (University of Pennsylvania School of Medicine)

  • Hiroshi Kameda

    (Juntendo University Graduate School of Medicine)

  • Masato Koike

    (Juntendo University Graduate School of Medicine)

  • Kelvin C. Luk

    (University of Pennsylvania School of Medicine)

  • John Q. Trojanowski

    (University of Pennsylvania School of Medicine)

  • Virginia M.-Y. Lee

    (University of Pennsylvania School of Medicine)

Abstract

Extraction of α-Synuclein (αSyn) aggregates from Lewy body disease (LBD) brains has been widely described yet templated fibrillization of LB-αSyn often fails to propagate its structural and functional properties. We recently demonstrated that aggregates amplified from LB-αSyn (ampLB) show distinct biological activities in vitro compared to human αSyn preformed fibrils (hPFF) formed de novo. Here we compare the in vivo biological activities of hPFF and ampLB regarding seeding activity, latency in inducing pathology, distribution of pathology, inclusion morphology, and cell-type preference. Injection of ampLB into mice expressing only human αSyn (male Thy1:SNCA/Snca–/– mice) induced pathologies similar to those of LBD subjects that were distinct from those induced by hPFF-injection or developing spontaneously with aging. Importantly, αSyn aggregates in ampLB-injected Thy1:SNCA/Snca–/– mice maintained the unique biological and conformational features of original LB-αSyn. These results indicate that ampLB-injection, rather than conventional PFF-injection or αSyn overexpression, faithfully models key aspects of LBD.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-42705-5
    DOI: 10.1038/s41467-023-42705-5
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    References listed on IDEAS

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    1. W. Peelaerts & L. Bousset & A. Van der Perren & A. Moskalyuk & R. Pulizzi & M. Giugliano & C. Van den Haute & R. Melki & V. Baekelandt, 2015. "α-Synuclein strains cause distinct synucleinopathies after local and systemic administration," Nature, Nature, vol. 522(7556), pages 340-344, June.
    2. Benedict Tanudjojo & Samiha S. Shaikh & Alexis Fenyi & Luc Bousset & Devika Agarwal & Jade Marsh & Christos Zois & Sabrina Heman-Ackah & Roman Fischer & David Sims & Ronald Melki & George K. Tofaris, 2021. "Phenotypic manifestation of α-synuclein strains derived from Parkinson’s disease and multiple system atrophy in human dopaminergic neurons," Nature Communications, Nature, vol. 12(1), pages 1-16, December.
    3. 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.
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