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Cell-to-cell transmission of toxic forms of α-Synuclein (αS) is thought to underlie disease progression in Parkinson disease. αS in humans is constitutively N-terminally acetylated (αS acetyl ), although the impact of this modification is relatively unexplored. Here, we report that αS acetyl  is more effective at inducing intracellular aggregation in primary neurons than unmodified αS (αS un ). We identify complex N-linked glycans as binding partners for αS acetyl  and demonstrate that cellular internalization of αS acetyl  is reduced significantly upon cleavage of extracellular N-linked glycans, but not other carbohydrates. We verify binding of αS acetyl  to N-linked glycans in vitro, using both isolated glycans and cell-derived proteoliposomes. Finally, we identify neurexin 1β, a neuronal glycoprotein, as capable of driving glycan-dependent uptake of αS acetyl . Importantly, our results are specific to αS acetyl  because αS un  does not demonstrate sensitivity for N-linked glycans in any of our assays. Our study identifies extracellular N-linked glycans—and the glycoprotein neurexin 1β specifically—as key modulators of neuronal uptake of αS acetyl , drawing attention to the potential therapeutic value of αS acetyl -glycan interactions.

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