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α-Synuclein fibril-specific nanobody reduces prion-like α-synuclein spreading in mice

Author

Listed:
  • Yemima R. Butler

    (Life Sciences Institute, University of Michigan
    University of Michigan)

  • Yuqing Liu

    (Johns Hopkins University School of Medicine
    Johns Hopkins University School of Medicine
    Tsinghua University)

  • Ramhari Kumbhar

    (Johns Hopkins University School of Medicine
    Johns Hopkins University School of Medicine)

  • Peiran Zhao

    (Life Sciences Institute, University of Michigan)

  • Kundlik Gadhave

    (Johns Hopkins University School of Medicine
    Johns Hopkins University School of Medicine)

  • Ning Wang

    (Johns Hopkins University School of Medicine
    Johns Hopkins University School of Medicine)

  • Yanmei Li

    (Tsinghua University)

  • Xiaobo Mao

    (Johns Hopkins University School of Medicine
    Johns Hopkins University School of Medicine)

  • Wenjing Wang

    (Life Sciences Institute, University of Michigan
    University of Michigan)

Abstract

Pathogenic α-synuclein (α-syn) is a prion-like protein that drives the pathogenesis of Lewy Body Dementia (LBD) and Parkinson’s Disease (PD). To target pathogenic α-syn preformed fibrils (PFF), here we designed extracellular disulfide bond-free synthetic nanobody libraries in yeast. Following selection, we identified a nanobody, PFFNB2, that can specifically recognize α-syn PFF over α-syn monomers. PFFNB2 cannot inhibit the aggregation of α-syn monomer, but can significantly dissociate α-syn fibrils. Furthermore, adeno-associated virus (AAV)-encoding EGFP fused to PFFNB2 (AAV-EGFP-PFFNB2) can inhibit PFF-induced α-syn serine 129 phosphorylation (pS129) in mouse primary cortical neurons, and prevent α-syn pathology spreading to the cortex in the transgenic mice expressing human wild type (WT) α-syn by intrastriatal-PFF injection. The pS129 immunoreactivity is negatively correlated with the expression of AAV-EGFP-PFFNB2. In conclusion, PFFNB2 holds a promise for mechanistic exploration and therapeutic development in α-syn-related pathogenesis.

Suggested Citation

  • Yemima R. Butler & Yuqing Liu & Ramhari Kumbhar & Peiran Zhao & Kundlik Gadhave & Ning Wang & Yanmei Li & Xiaobo Mao & Wenjing Wang, 2022. "α-Synuclein fibril-specific nanobody reduces prion-like α-synuclein spreading in mice," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-31787-2
    DOI: 10.1038/s41467-022-31787-2
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    References listed on IDEAS

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    1. Tim Bartels & Joanna G. Choi & Dennis J. Selkoe, 2011. "α-Synuclein occurs physiologically as a helically folded tetramer that resists aggregation," Nature, Nature, vol. 477(7362), pages 107-110, September.
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