α-Synuclein Binds Extracellular Complex N-Linked Glycans

Abstract

Fibrillar deposits of α-Synuclein (αS) are the hallmark of Parkinson's disease. While significant efforts have focused on deciphering pathological mechanisms of αS, comparatively little is understood of its native function. Recent evidence suggests that disease may propagate through cell-to-cell transmission of toxic forms of αS. Relevant to this mechanism, our work reports on the discovery that αS binds extracellular N-linked glycans. We find that αS binds to proteoliposomes derived from neuronal-lineage cells and that removal of N-linked glycans both decreases binding and alters the conformation of bound αS. Cellular internalization of both monomer and fibrillar αS is specific to neuronal-lineage cells is reduced dramatically upon cleavage of extracellular N-linked glycans. Cleavage of extracellular glycans from primary neurons reduces the uptake of αS by >10 fold. Importantly, all of our results are specific to N-terminally acetylated αS, the physiologically relevant form of the protein. Our results suggest that interactions with extracellular glycans may play an important role in cellular uptake of αS relevant both to normal proteostasis as well as to transmission of pathogenic αS species.