Mechanistic basis for receptor-mediated pathological α-synuclein fibril cell-to-cell transmission in Parkinson's disease

Abstract

Significance Receptor-mediated cell-to-cell transmission of pathological α-synuclein (α-syn) plays an important role in the progression of Parkinson’s disease (PD). We show that α-syn uses its acidic C terminus to bind an alkaline patch on the receptors. The formation of amyloid fibrils dramatically enhances the binding by condensing α-syn molecules and better exposing the C terminus. Moreover, S129 phosphorylation, a hallmark modification of α-syn accumulation in Lewy bodies, further strengthens the electrostatic interactions between α-syn and the receptors, which accelerates the PD-like pathology in mice. This work illuminates mechanistic understanding on the spread of pathological proteins and provides structural information for the therapeutic targeting of pathological α-syn spread in PD progression.