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

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.