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

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. [ABSTRACT FROM AUTHOR]