α-Synuclein is a Neuron Specific Lectin

Abstract

Monomeric α-Synuclein (αS) is a small intrinsically disordered, neuronal protein which garners significant interest in the biomedical field because fibrillar deposits of αS are the hallmark of Parkinson's disease (PD). While significant efforts have focused on deciphering pathological mechanisms of αS, comparatively little is understood of its native function. Our work identifies that αS is a lectin that binds specifically to complex, N-linked glycans. Using cell-derived proteoliposomes, we find that αS associates selectively with neuronal-lineage cell membranes and induces vesicle clustering. Cleavage of surface exposed N-linked glycans decreases αS binding to the membrane, disrupts vesicle crowding and alters the conformation of bound protein. An array-based screen identified a small number of pentasaccharide-core glycans, underscoring the specificity of the interaction. Intriguingly, only the N-terminally acetylated, physiological form of the protein is impacted by deglycosylation and returns hits in the glycan-array screen. Recent findings indicate that αS pathology spreads into the brain and monomeric, oligomeric and fibrillar αS can progress from cell to cell and trigger the aggregation of the endogenous protein in recipient neurons. Cellular internalization of αS is specific to neuronal-lineage cells and we identify that this is dependent upon cell-surface N-linked glycans. PD-relevant αS mutants also show reduced cellular uptake and deficient glycan binding. The classification of αS as an intrinsically disordered lectin provides new considerations for understanding its long-sought native function and role in disease, as well as for αS-targeted therapeutics for treatment of PD.