发病机制
纤维
转基因小鼠
转基因
化学
丝氨酸
α-突触核蛋白
细胞生物学
共核细胞病
路易体
磷酸化
HEK 293细胞
帕金森病
生物
生物化学
基因
医学
疾病
病理
免疫学
作者
Yemima R. Butler,Yuqing Liu,Ramhari Kumbhar,Peiran Zhao,Kundlik Gadhave,Ning Wang,Yan-Mei Li,Xiaobo Mao,Wenjing Wang
标识
DOI:10.1038/s41467-022-31787-2
摘要
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.
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