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Yet, under nonpathological conditions, monomeric \u03b1-syn is hypothesized to exist in an equilibrium between disordered cytosolic- and partially \u03b1-helical lipid-bound states: a feature presumably important in synaptic vesicle release machinery. The exact underlying role of \u03b1-syn in these processes, and the mechanisms regulating membrane-binding of \u03b1-syn remains poorly understood. Herein we demonstrate that Protein kinase R (PKR) can phosphorylate \u03b1-syn at several Ser\/Thr residues located in the membrane-binding region that is essential for \u03b1-syn's vesicle-interactions. \u03b1-Syn phosphorylated by PKR or \u03b1-syn isolated from PKR overexpressing cells, exhibit decreased binding to lipid membranes. Phosphorylation of Thr64 and Thr72 appears as the major contributor to this effect, as the phosphomimetic Thr64Glu\/Thr72Glu-\u03b1-syn mutant displays reduced overall attachment to brain vesicles due to a decrease in vesicle-affinity of the last two thirds of \u03b1-syn's membrane binding region. This allows enhancement of the \u201cdouble-anchor\u201d vesicle-binding mechanism that tethers two vesicles and thus promote the clustering of presynaptic vesicles in vitro. Furthermore, phosphomimetic Thr64Glu\/Thr72Glu-\u03b1-syn inhibits \u03b1-syn oligomerization and completely abolishes nucleation, elongation, and seeding of \u03b1-syn fibrillation in vitro and in cells, and prevents trans-synaptic spreading of aggregated \u03b1-syn pathology in organotypic hippocampal slice cultures. Overall, our findings demonstrate that normal and abnormal functions of \u03b1-syn, like membrane-binding, synaptic vesicle clustering and aggregation can be regulated by phosphorylation, e.g., via PKR. Mechanisms that could potentially be modulated for the benefit of patients suffering from \u03b1-syn aggregate-related diseases.<\/jats:p>","DOI":"10.1093\/pnasnexus\/pgac259","type":"journal-article","created":{"date-parts":[[2022,11,17]],"date-time":"2022-11-17T02:13:10Z","timestamp":1668651190000},"source":"Crossref","is-referenced-by-count":14,"title":["Protein kinase R dependent phosphorylation of \u03b1-synuclein regulates its membrane binding and aggregation"],"prefix":"10.1093","volume":"1","author":[{"given":"Lasse","family":"Reimer","sequence":"first","affiliation":[{"name":"Danish Research Institute of Translational Neuroscience - DANDRITE, Aarhus University , 8000 Aarhus C , Denmark"},{"name":"Department of Biomedicine, Aarhus University , 8000 Aarhus C , Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hjalte","family":"Gram","sequence":"additional","affiliation":[{"name":"Danish Research Institute of Translational Neuroscience - DANDRITE, Aarhus University , 8000 Aarhus C , Denmark"},{"name":"Department of Biomedicine, Aarhus University , 8000 Aarhus C , Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1177-5197","authenticated-orcid":false,"given":"Nanna M\u00f8ller","family":"Jensen","sequence":"additional","affiliation":[{"name":"Danish Research Institute of Translational Neuroscience - DANDRITE, Aarhus University , 8000 Aarhus C , Denmark"},{"name":"Department of Biomedicine, Aarhus University , 8000 Aarhus C , Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristine","family":"Betzer","sequence":"additional","affiliation":[{"name":"Danish Research Institute of Translational Neuroscience - DANDRITE, Aarhus University , 8000 Aarhus C , Denmark"},{"name":"Department of Biomedicine, Aarhus University , 8000 Aarhus C , Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Washington School of Medicine , Seattle WA 98195 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lorrain","family":"Jin","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Washington School of Medicine , Seattle WA 98195 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6901-2558","authenticated-orcid":false,"given":"Min","family":"Shi","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Washington School of Medicine , Seattle WA 98195 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Driss","family":"Boudeffa","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular and Chemical Biology of Neurodegeneration, School of Life Sciences Brain Mind Institute , Station 19, 1015 Lausanne , Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuliana","family":"Fusco","sequence":"additional","affiliation":[{"name":"Centre for Misfolding Diseases,Department of Chemistry, University of Cambridge , CB2 1EW , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alfonso","family":"De\u00a0Simone","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, University of Naples , 80131, Naples , Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deniz","family":"Kirik","sequence":"additional","affiliation":[{"name":"Brain Repair and Imaging in Neural Systems, Department of Experimental Medical Science, Lund University , 22184 Lund , Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hilal A","family":"Lashuel","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular and Chemical Biology of Neurodegeneration, School of Life Sciences Brain Mind Institute , Station 19, 1015 Lausanne , Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Washington School of Medicine , Seattle WA 98195 , USA"},{"name":"Department of Pathology, Zhejiang University School of Medicine and the First Affiliated Hospital , 310003 Hangzhou , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4439-9020","authenticated-orcid":false,"given":"Poul Henning","family":"Jensen","sequence":"additional","affiliation":[{"name":"Danish Research Institute of Translational Neuroscience - DANDRITE, Aarhus University , 8000 Aarhus C , Denmark"},{"name":"Department of Biomedicine, Aarhus University , 8000 Aarhus C , 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