查找使用阿拉丁产品的科研文献

Soluble N-terminal region of prion protein causes rapid neurodegeneration in prion disease

Runchuan Yan,Yan Zhang,Jingjing Zhang,Xiangyi Zhang,Yue Han,Mengfei Wang,Dan Wang,Shengnan Huang,Wei Liu,Qi Shi,Xiaoping Dong,Wen-Quan Zou,Zhen Li,Jiyan Ma

Rapid neurodegeneration distinguishes prion disease from other neurodegenerative disorders. Notably, normal prion protein (PrP C ) is essential for prion-induced rapid neurodegeneration, but the underlying mechanism remains unknown. Here, we show that the unstructured N-terminal region of PrP C induces rapid and lethal neurodegeneration in mice, accompanied by the hallmark of prion disease, spongiosis. The neurotoxic N-terminal PrP is soluble, associates peripherally with lipid membranes, and induces neurotoxicity only when a critical threshold is exceeded. Both the N-terminally localized KKRPKP sequence and octarepeats contribute to neurotoxicity, with KKRPKP being essential. Without it, the N-terminal PrP is innocuous but exacerbates either neurodegeneration caused by N-terminal PrP or neurodegeneration in prion disease induced by intracerebral prion inoculation in mice. Our findings establish that soluble N-terminal PrP causes rapid neurodegeneration in prion disease and is a target for intervention.