Abstract
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 (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 1β, a neuronal glycoprotein, as capable of driving glycan-dependent uptake of αSacetyl. Importantly, our results are specific to αSacetyl because αSun 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 αSacetyl, drawing attention to the potential therapeutic value of αSacetyl-glycan interactions.
Highlights
The pathologies of Parkinson disease and related synucleinopathies are characterized by the accumulation of aggregates of the neuronal protein α-Synuclein [1]
To determine whether N-terminal acetylation of αS alters this seeding behavior, primary hippocampal neurons were incubated with preformed fibrils (PFFs) of αSacetyl or unmodified αS (αSun) [21] (S1 Fig)
For αSun PFFs, the time course was in good agreement with previously published studies [21]; aggregates were observed in axons by day 7 and had spread to somatodendritic compartments by day 10
Summary
The pathologies of Parkinson disease and related synucleinopathies are characterized by the accumulation of aggregates of the neuronal protein α-Synuclein (αS) [1]. Emerging evidence suggests that cellto-cell transmission of toxic αS species may be the basis of disease propagation [3]. It associates peripherally to anionic lipid bilayers through its N-terminal domain, which becomes αhelical upon binding [5]. The localization of αS to nerve terminals [6,7] and to cellular lipid raft domains [8] suggests that there are components or properties of cellular membranes that are important for αS binding and function that may not be fully reproduced by simple lipid mixtures. Specific components of the extracellular membrane, including proteins [9] and proteoglycans [10], have been identified as having roles in the uptake of pathogenic αS species
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