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

Yemima R. Butler, Yuqing Liu, Ramhari Kumbhar, Peiran Zhao, Kundlik Gadhave, Ning Wang, Yanmei Li, Xiaobo Mao () and Wenjing Wang ()
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Yemima R. Butler: Life Sciences Institute, University of Michigan
Yuqing Liu: Johns Hopkins University School of Medicine
Ramhari Kumbhar: Johns Hopkins University School of Medicine
Peiran Zhao: Life Sciences Institute, University of Michigan
Kundlik Gadhave: Johns Hopkins University School of Medicine
Ning Wang: Johns Hopkins University School of Medicine
Yanmei Li: Tsinghua University
Xiaobo Mao: Johns Hopkins University School of Medicine
Wenjing Wang: Life Sciences Institute, University of Michigan

Nature Communications, 2022, vol. 13, issue 1, 1-13

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-31787-2

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