Alpha‐synuclein binds to neuron‐specific glycans

Abstract

Fibrillar deposits of the intrinsically disordered protein α‐Synuclein (αS) are the defining pathological feature of Parkinson's disease, the second most common neurodegenerative disorder. αS is abundant in the brain, where its localization to presynaptic termini and ability to stabilize curved membranes support a role in synaptic vesicle exocytosis/endocytosis, although its precise function is not known. N‐terminal acetylation is universally present on αS in vivo, in samples derived from both healthy persons and Parkinson's disease patients. Prior work from our group and others have demonstrated that N‐terminal acetylation (αSacetyl) impacts the fundamental biophysical properties of αS. Here, using cell‐derived proteolipid vesicles, we find that αSacetyl binds specifically to neuronal‐lineage cell membranes. Cleavage of complex N‐linked glycans dramatically decreases binding by αSacetyl while having a negligible impact on binding by the unmodified protein, αSunmod. αSacetyl selectively binds to glycans cleaved from cultured neuronal cells and removal of cell‐surface glycans dramatically reduces its cellular uptake. Based on these findings we propose that N‐terminal acetylation confers glycan recognition and binding to αS and that it is a critical modification for functional interactions with cellular protein binding partners. Moreover, understanding the basis of this interaction may have critical implications in obtaining a clearer understanding in the function of αSacetyl.Support or Funding InformationNIH NINDS NS079955This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.