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Identification of N-linked glycans as specific mediators of neuronal uptake of acetylated α-Synuclein.
- Source :
- PLoS Biology; 6/18/2019, Vol. 17 Issue 6, p1-29, 29p, 7 Graphs
- Publication Year :
- 2019
-
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 (αS<subscript>acetyl</subscript>), although the impact of this modification is relatively unexplored. Here, we report that αS<subscript>acetyl</subscript> is more effective at inducing intracellular aggregation in primary neurons than unmodified αS (αS<subscript>un</subscript>). We identify complex N-linked glycans as binding partners for αS<subscript>acetyl</subscript> and demonstrate that cellular internalization of αS<subscript>acetyl</subscript> is reduced significantly upon cleavage of extracellular N-linked glycans, but not other carbohydrates. We verify binding of αS<subscript>acetyl</subscript> 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 αS<subscript>acetyl</subscript>. Importantly, our results are specific to αS<subscript>acetyl</subscript> because αS<subscript>un</subscript> 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 αS<subscript>acetyl</subscript>, drawing attention to the potential therapeutic value of αS<subscript>acetyl</subscript>-glycan interactions. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 15449173
- Volume :
- 17
- Issue :
- 6
- Database :
- Complementary Index
- Journal :
- PLoS Biology
- Publication Type :
- Academic Journal
- Accession number :
- 137045029
- Full Text :
- https://doi.org/10.1371/journal.pbio.3000318