TY - JOUR T1 - Identification of N-linked glycans as specific mediators of neuronal uptake of acetylated α-Synuclein JF - bioRxiv DO - 10.1101/407247 SP - 407247 AU - Melissa Birol AU - Slawomir P. Wojcik AU - Andrew D. Miranker AU - Elizabeth Rhoades Y1 - 2018/01/01 UR - http://biorxiv.org/content/early/2018/12/09/407247.abstract N2 - Cell-to-cell transmission of toxic forms of α-Synuclein (αS) is thought to underlie disease progression in Parkinson’s disease. αS in humans is constitutively N-terminally acetylated (αSacetyl), although the impact of this modification is relatively unexplored. Here we report that αSacetyl is more effective at inducing intracellular aggregation in primary neurons than unmodified αS (αSun). We identify complex N-linked glycans as binding partners for αSacetyl, and demonstrate that cellular internalization of αSacetyl is reduced significantly upon cleavage of extracellular N-linked glycans, but not other carbohydrates. We verify binding of αSacetyl to N-linked glycans in vitro, using both isolated glycans and cell-derived proteoliposomes. Finally, we identify neurexin lβ, a neuronal glycoprotein, as capable of driving glycan-dependent uptake of αSacetyl. Importantly, our results are specific to αSacetyl as αSun does not demonstrate sensitivity for N-linked glycans. Our study identifies extracellular N-linked glycans, and neurexin lβ specifically, as key modulators of neuronal uptake of physiological αSacetyl drawing attention to the potential therapeutic value of αSacetyl-glycan interactions. ER -