Effects of Serine 129 Phosphorylation on α-Synuclein Aggregation, Membrane Association, and Internalization*
Identifieur interne : 000745 ( Main/Exploration ); précédent : 000744; suivant : 000746Effects of Serine 129 Phosphorylation on α-Synuclein Aggregation, Membrane Association, and Internalization*
Auteurs : Filsy Samuel ; William P. Flavin ; Sobia Iqbal ; Consiglia Pacelli ; Sri Dushyaanthan Sri Renganathan ; Louis-Eric Trudeau ; Edward M. Campbell [États-Unis] ; Paul E. Fraser ; Anurag Tandon [Canada]Source :
- The Journal of Biological Chemistry [ 0021-9258 ] ; 2015.
English descriptors
- KwdEn :
- Amino Acid Substitution, Animals, Animals, Newborn, Cell Line, Cells, Cultured, Dopaminergic Neurons (cytology), Dopaminergic Neurons (metabolism), Dopaminergic Neurons (pathology), Endocytosis, Humans, Mesencephalon (cytology), Mesencephalon (metabolism), Mesencephalon (pathology), Mice, Mutation, Parkinson Disease (genetics), Parkinson Disease (metabolism), Parkinson Disease (pathology), Phosphorylation, Protein Aggregation, Pathological (genetics), Protein Aggregation, Pathological (metabolism), Protein Aggregation, Pathological (pathology), Protein Folding, Protein Processing, Post-Translational, Protein-Serine-Threonine Kinases (genetics), Protein-Serine-Threonine Kinases (metabolism), Recombinant Fusion Proteins (genetics), Recombinant Fusion Proteins (metabolism), Recombinant Proteins (chemistry), Recombinant Proteins (genetics), Recombinant Proteins (metabolism), Serine (metabolism), Synaptosomes (metabolism), Synaptosomes (pathology), alpha-Synuclein (chemistry), alpha-Synuclein (genetics), alpha-Synuclein (metabolism).
- MESH :
- chemical , chemistry : Recombinant Proteins, alpha-Synuclein.
- chemical , genetics : Protein-Serine-Threonine Kinases, Recombinant Fusion Proteins, Recombinant Proteins, alpha-Synuclein.
- cytology : Dopaminergic Neurons, Mesencephalon.
- genetics : Parkinson Disease, Protein Aggregation, Pathological.
- metabolism : Dopaminergic Neurons, Mesencephalon, Parkinson Disease, Protein Aggregation, Pathological, Protein-Serine-Threonine Kinases, Recombinant Fusion Proteins, Recombinant Proteins, Serine, Synaptosomes, alpha-Synuclein.
- pathology : Dopaminergic Neurons, Mesencephalon, Parkinson Disease, Protein Aggregation, Pathological, Synaptosomes.
- Amino Acid Substitution, Animals, Animals, Newborn, Cell Line, Cells, Cultured, Endocytosis, Humans, Mice, Mutation, Phosphorylation, Protein Folding, Protein Processing, Post-Translational.
Abstract
Although trace levels of phosphorylated α-synuclein (α-syn) are detectable in normal brains, nearly all α-syn accumulated within Lewy bodies in Parkinson disease brains is phosphorylated on serine 129 (Ser-129). The role of the phosphoserine residue and its effects on α-syn structure, function, and intracellular accumulation are poorly understood. Here, co-expression of α-syn and polo-like kinase 2 (PLK2), a kinase that targets Ser-129, was used to generate phosphorylated α-syn for biophysical and biological characterization. Misfolding and fibril formation of phosphorylated α-syn isoforms were detected earlier, although the fibrils remained phosphatase- and protease-sensitive. Membrane binding of α-syn monomers was differentially affected by phosphorylation depending on the Parkinson disease-linked mutation. WT α-syn binding to presynaptic membranes was not affected by phosphorylation, whereas A30P α-syn binding was greatly increased, and A53T α-syn was slightly lower, implicating distal effects of the carboxyl- on amino-terminal membrane binding. Endocytic vesicle-mediated internalization of pre-formed fibrils into non-neuronal cells and dopaminergic neurons matched the efficacy of α-syn membrane binding. Finally, the disruption of internalized vesicle membranes was enhanced by the phosphorylated α-syn isoforms, a potential means for misfolded extracellular or lumenal α-syn to access cytosolic α-syn. Our results suggest that the threshold for vesicle permeabilization is evident even at low levels of α-syn internalization and are relevant to therapeutic strategies to reduce intercellular propagation of α-syn misfolding.
Url:
DOI: 10.1074/jbc.M115.705095
PubMed: 26719332
PubMed Central: 4813466
Affiliations:
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Le document en format XML
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Flavin</name><affiliation><nlm:aff id="aff2"></nlm:aff></affiliation></author><author><name sortKey="Iqbal, Sobia" sort="Iqbal, Sobia" uniqKey="Iqbal S" first="Sobia" last="Iqbal">Sobia Iqbal</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Pacelli, Consiglia" sort="Pacelli, Consiglia" uniqKey="Pacelli C" first="Consiglia" last="Pacelli">Consiglia Pacelli</name><affiliation><nlm:aff id="aff4"></nlm:aff></affiliation></author><author><name sortKey="Sri Renganathan, Sri Dushyaanthan" sort="Sri Renganathan, Sri Dushyaanthan" uniqKey="Sri Renganathan S" first="Sri Dushyaanthan" last="Sri Renganathan">Sri Dushyaanthan Sri Renganathan</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Trudeau, Louis Eric" sort="Trudeau, Louis Eric" uniqKey="Trudeau L" first="Louis-Eric" last="Trudeau">Louis-Eric Trudeau</name><affiliation><nlm:aff id="aff4"></nlm:aff></affiliation></author><author><name sortKey="Campbell, Edward M" sort="Campbell, Edward M" uniqKey="Campbell E" first="Edward M." last="Campbell">Edward M. 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The role of the phosphoserine residue and its effects on α-syn structure, function, and intracellular accumulation are poorly understood. Here, co-expression of α-syn and polo-like kinase 2 (PLK2), a kinase that targets Ser-129, was used to generate phosphorylated α-syn for biophysical and biological characterization. Misfolding and fibril formation of phosphorylated α-syn isoforms were detected earlier, although the fibrils remained phosphatase- and protease-sensitive. Membrane binding of α-syn monomers was differentially affected by phosphorylation depending on the Parkinson disease-linked mutation. WT α-syn binding to presynaptic membranes was not affected by phosphorylation, whereas A30P α-syn binding was greatly increased, and A53T α-syn was slightly lower, implicating distal effects of the carboxyl- on amino-terminal membrane binding. Endocytic vesicle-mediated internalization of pre-formed fibrils into non-neuronal cells and dopaminergic neurons matched the efficacy of α-syn membrane binding. Finally, the disruption of internalized vesicle membranes was enhanced by the phosphorylated α-syn isoforms, a potential means for misfolded extracellular or lumenal α-syn to access cytosolic α-syn. Our results suggest that the threshold for vesicle permeabilization is evident even at low levels of α-syn internalization and are relevant to therapeutic strategies to reduce intercellular propagation of α-syn misfolding.</p></div></front></TEI><affiliations><list><country><li>Canada</li><li>États-Unis</li></country><region><li>Illinois</li><li>Ontario</li></region><settlement><li>Toronto</li></settlement><orgName><li>Université de Toronto</li></orgName></list><tree><noCountry><name sortKey="Flavin, William P" sort="Flavin, William P" uniqKey="Flavin W" first="William P." last="Flavin">William P. Flavin</name><name sortKey="Fraser, Paul E" sort="Fraser, Paul E" uniqKey="Fraser P" first="Paul E." last="Fraser">Paul E. Fraser</name><name sortKey="Iqbal, Sobia" sort="Iqbal, Sobia" uniqKey="Iqbal S" first="Sobia" last="Iqbal">Sobia Iqbal</name><name sortKey="Pacelli, Consiglia" sort="Pacelli, Consiglia" uniqKey="Pacelli C" first="Consiglia" last="Pacelli">Consiglia Pacelli</name><name sortKey="Samuel, Filsy" sort="Samuel, Filsy" uniqKey="Samuel F" first="Filsy" last="Samuel">Filsy Samuel</name><name sortKey="Sri Renganathan, Sri Dushyaanthan" sort="Sri Renganathan, Sri Dushyaanthan" uniqKey="Sri Renganathan S" first="Sri Dushyaanthan" last="Sri Renganathan">Sri Dushyaanthan Sri Renganathan</name><name sortKey="Trudeau, Louis Eric" sort="Trudeau, Louis Eric" uniqKey="Trudeau L" first="Louis-Eric" last="Trudeau">Louis-Eric Trudeau</name></noCountry><country name="États-Unis"><region name="Illinois"><name sortKey="Campbell, Edward M" sort="Campbell, Edward M" uniqKey="Campbell E" first="Edward M." last="Campbell">Edward M. Campbell</name></region></country><country name="Canada"><region name="Ontario"><name sortKey="Tandon, Anurag" sort="Tandon, Anurag" uniqKey="Tandon A" first="Anurag" last="Tandon">Anurag Tandon</name></region></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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