Identification of N-linked glycans as specific mediators of neuronal uptake of acetylated α-Synuclein

Abstract

Cell-to-cell transmission of toxic forms of -Synuclein (S) is thought to underlie disease progression in Parkinsons disease. S in humans is constitutively N-terminally acetylated (Sacetyl), although the impact of this modification is relatively unexplored. Here we report that Sacetyl is more effective at inducing intracellular aggregation in primary neurons than unmodified S (Sun). We identify complex N-linked glycans as binding partners for Sacetyl, and demonstrate that cellular internalization of Sacetyl is reduced significantly upon cleavage of extracellular N-linked glycans, but not other carbohydrates. We verify binding of Sacetyl to N-linked glycans in vitro, using both isolated glycans and cell-derived proteoliposomes. Finally, we identify neurexin l{beta}, a neuronal glycoprotein, as capable of driving glycan-dependent uptake of Sacetyl. Importantly, our results are specific to Sacetyl as Sun does not demonstrate sensitivity for N-linked glycans. Our study identifies extracellular N-linked glycans, and neurexin l{beta} specifically, as key modulators of neuronal uptake of physiological Sacetyl drawing attention to the potential therapeutic value of Sacetyl-glycan interactions.