The localization of αS to nerve terminals and to cellular lipid raft domains 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. It associates peripherally to anionic lipid bilayers through its N-terminal domain, which becomes α-helical upon binding. ΑS is a small, soluble protein that is intrinsically disordered in the cytoplasm. Emerging evidence suggests that cell-to-cell transmission of toxic αS species may be the basis of disease propagation. The prevailing hypothesis is that toxicity is mediated by prefibrillar oligomers of αS. The pathologies of Parkinson disease and related synucleinopathies are characterized by the accumulation of aggregates of the neuronal protein α-Synuclein (αS). Penn Medicine Translational Neuroscience Center SH-SY5Y, Matrix-assisted laser desorption/ionization NatB, Institutional Animal Care and Use Committee LAG3, Heteronuclear single quantum coherence IACUC, ΑS fluorescently labeled with AL594 con A,ĭulbecco's Modified Eagle's Medium eGFP,Įnhanced green fluorescent protein Endo H,įluorescence correlation spectroscopy FLIM,įluorescence lifetime imaging microscopy FRET,įörster resonance energy transfer GdmCl, ΑS fluorescently labeled with AL488 αS-AL594, ΑS phosphorylated at serine 129 αSacetyl, Fox Foundation (to ER) The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Ĭompeting interests: The authors have declared that no competing interests exist. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.ĭata Availability: All relevant data are within the paper and its Supporting Information files.įunding: National Institutes of Health R01 NS079955 (to ER) Michael J. Received: DecemAccepted: Published: June 18, 2019Ĭopyright: © 2019 Birol et al. Bates, University College London Institute of Neurology, UNITED KINGDOM PLoS Biol 17(6):Īcademic Editor: Gillian P. Our study identifies extracellular N-linked glycans-and the glycoprotein neurexin 1β specifically-as key modulators of neuronal uptake of αS acetyl, drawing attention to the potential therapeutic value of αS acetyl-glycan interactions.Ĭitation: Birol M, Wojcik SP, Miranker AD, Rhoades E (2019) Identification of N-linked glycans as specific mediators of neuronal uptake of acetylated α-Synuclein. Importantly, our results are specific to αS acetyl because αS un does not demonstrate sensitivity for N-linked glycans in any of our assays. Finally, we identify neurexin 1β, a neuronal glycoprotein, as capable of driving glycan-dependent uptake of αS acetyl. We verify binding of αS acetyl to N-linked glycans in vitro, using both isolated glycans and cell-derived proteoliposomes. We identify complex N-linked glycans as binding partners for αS acetyl and demonstrate that cellular internalization of αS acetyl is reduced significantly upon cleavage of extracellular N-linked glycans, but not other carbohydrates. Here, we report that αS acetyl is more effective at inducing intracellular aggregation in primary neurons than unmodified αS (αS un). αS in humans is constitutively N-terminally acetylated (αS acetyl), although the impact of this modification is relatively unexplored. Reson., 90, 405–410.Cell-to-cell transmission of toxic forms of α-Synuclein (αS) is thought to underlie disease progression in Parkinson disease. ![]() Kristensen, S.M., Munk Jørgensen, A.M., Led, J.J., Balschmidt, P. Kay, L.E., Brooks, B., Sparks, S.W., Torchia, D.A. Hoch, J.C.) NATO ASI series A, Plenum, New York, NY, in press. (1991) Computational Aspects of the Study of Biological Macromolecules by Nuclear Magnetic Resonance Spectroscopy (Ed. (1987) Principles of Nuclear Magnetic Resonance in One and Two Dimensions, Clarendon, Oxford, pp.
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