Identification of synaptosomal proteins binding to monomeric and oligomeric α-synuclein

Monomeric α-synuclein (αSN) species are abundant in nerve terminals where they are hypothesized to play a physiological role related to synaptic vesicle turn-over. In Parkinson's disease (PD) and dementia with Lewy body (DLB), αSN accumulates as aggregated soluble oligomers in terminals, axons...

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Veröffentlicht in:PloS one 2015-02, Vol.10 (2), p.e0116473-e0116473
Hauptverfasser: Betzer, Cristine, Movius, A James, Shi, Min, Gai, Wei-Ping, Zhang, Jing, Jensen, Poul Henning
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Movius, A James
Shi, Min
Gai, Wei-Ping
Zhang, Jing
Jensen, Poul Henning
description Monomeric α-synuclein (αSN) species are abundant in nerve terminals where they are hypothesized to play a physiological role related to synaptic vesicle turn-over. In Parkinson's disease (PD) and dementia with Lewy body (DLB), αSN accumulates as aggregated soluble oligomers in terminals, axons and the somatodendritic compartment and insoluble filaments in Lewy inclusions and Lewy neurites. The autosomal dominant heritability associated to mutations in the αSN gene suggest a gain of function associated to aggregated αSN. We have conducted a proteomic screen to identify the αSN interactome in brain synaptosomes. Porcine brain synaptosomes were fractionated, solubilized in non-denaturing detergent and subjected to co-immunoprecipitation using purified recombinant human αSN monomers or oligomers as bait. The isolated αSN binding proteins were identified with LC-LTQ-orbitrap tandem mass spectrometry and quantified by peak area using Windows client application, Skyline Targeted Proteomic Environment. Data are available via ProteomeXchange with identifier PXD001462. To quantify the preferential binding an average fold increase was calculated by comparing binding to monomer and oligomer. We identified 10 proteins preferentially binding monomer, and 76 binding preferentially to oligomer and a group of 92 proteins not displaying any preferred conformation of αSN. The proteomic data were validated by immunoprecipitation in both human and porcine brain extracts using antibodies against monomer αSN interactors: Abl interactor 1, and myelin proteolipid protein, and oligomer interactors: glutamate decarboxylase 2, synapsin 1, glial fibrillary acidic protein, and VAMP-2. We demonstrate the existence of αSN conformation selective ligands and present lists of proteins, whose identity and functions will be useful for modeling normal and pathological αSN dependent processes.
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In Parkinson's disease (PD) and dementia with Lewy body (DLB), αSN accumulates as aggregated soluble oligomers in terminals, axons and the somatodendritic compartment and insoluble filaments in Lewy inclusions and Lewy neurites. The autosomal dominant heritability associated to mutations in the αSN gene suggest a gain of function associated to aggregated αSN. We have conducted a proteomic screen to identify the αSN interactome in brain synaptosomes. Porcine brain synaptosomes were fractionated, solubilized in non-denaturing detergent and subjected to co-immunoprecipitation using purified recombinant human αSN monomers or oligomers as bait. The isolated αSN binding proteins were identified with LC-LTQ-orbitrap tandem mass spectrometry and quantified by peak area using Windows client application, Skyline Targeted Proteomic Environment. Data are available via ProteomeXchange with identifier PXD001462. To quantify the preferential binding an average fold increase was calculated by comparing binding to monomer and oligomer. We identified 10 proteins preferentially binding monomer, and 76 binding preferentially to oligomer and a group of 92 proteins not displaying any preferred conformation of αSN. The proteomic data were validated by immunoprecipitation in both human and porcine brain extracts using antibodies against monomer αSN interactors: Abl interactor 1, and myelin proteolipid protein, and oligomer interactors: glutamate decarboxylase 2, synapsin 1, glial fibrillary acidic protein, and VAMP-2. We demonstrate the existence of αSN conformation selective ligands and present lists of proteins, whose identity and functions will be useful for modeling normal and pathological αSN dependent processes.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0116473</identifier><identifier>PMID: 25659148</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>alpha-Synuclein - chemistry ; alpha-Synuclein - metabolism ; Animals ; Antibodies ; Axons ; Binding ; Brain ; Brain - metabolism ; Brain research ; Data processing ; Dementia disorders ; Filaments ; Gene expression ; Glial fibrillary acidic protein ; Glutamate decarboxylase ; Heritability ; Humans ; Immunoprecipitation ; Lewy bodies ; Ligands ; Mass spectrometry ; Mass spectroscopy ; Medicine ; Mitochondria ; Monomers ; Movement disorders ; Mutation ; Myelin ; Myelin proteolipid protein ; Nerve endings ; Nerve Tissue Proteins - chemistry ; Nerve Tissue Proteins - metabolism ; Neurodegenerative diseases ; Neurosciences ; Oligomers ; Parkinson's disease ; Parkinsons disease ; Pathology ; Physiology ; Protein Binding ; Protein Multimerization ; Proteins ; Proteolipid protein ; Proteomics - methods ; Quantitative analysis ; Swine ; Synapsin ; Synaptosomes ; Synaptosomes - chemistry ; Synaptosomes - metabolism ; Synuclein ; Terminals</subject><ispartof>PloS one, 2015-02, Vol.10 (2), p.e0116473-e0116473</ispartof><rights>2015 Betzer et al. 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In Parkinson's disease (PD) and dementia with Lewy body (DLB), αSN accumulates as aggregated soluble oligomers in terminals, axons and the somatodendritic compartment and insoluble filaments in Lewy inclusions and Lewy neurites. The autosomal dominant heritability associated to mutations in the αSN gene suggest a gain of function associated to aggregated αSN. We have conducted a proteomic screen to identify the αSN interactome in brain synaptosomes. Porcine brain synaptosomes were fractionated, solubilized in non-denaturing detergent and subjected to co-immunoprecipitation using purified recombinant human αSN monomers or oligomers as bait. The isolated αSN binding proteins were identified with LC-LTQ-orbitrap tandem mass spectrometry and quantified by peak area using Windows client application, Skyline Targeted Proteomic Environment. Data are available via ProteomeXchange with identifier PXD001462. To quantify the preferential binding an average fold increase was calculated by comparing binding to monomer and oligomer. We identified 10 proteins preferentially binding monomer, and 76 binding preferentially to oligomer and a group of 92 proteins not displaying any preferred conformation of αSN. The proteomic data were validated by immunoprecipitation in both human and porcine brain extracts using antibodies against monomer αSN interactors: Abl interactor 1, and myelin proteolipid protein, and oligomer interactors: glutamate decarboxylase 2, synapsin 1, glial fibrillary acidic protein, and VAMP-2. We demonstrate the existence of αSN conformation selective ligands and present lists of proteins, whose identity and functions will be useful for modeling normal and pathological αSN dependent processes.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>25659148</pmid><doi>10.1371/journal.pone.0116473</doi><oa>free_for_read</oa></addata></record>
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subjects alpha-Synuclein - chemistry
alpha-Synuclein - metabolism
Animals
Antibodies
Axons
Binding
Brain
Brain - metabolism
Brain research
Data processing
Dementia disorders
Filaments
Gene expression
Glial fibrillary acidic protein
Glutamate decarboxylase
Heritability
Humans
Immunoprecipitation
Lewy bodies
Ligands
Mass spectrometry
Mass spectroscopy
Medicine
Mitochondria
Monomers
Movement disorders
Mutation
Myelin
Myelin proteolipid protein
Nerve endings
Nerve Tissue Proteins - chemistry
Nerve Tissue Proteins - metabolism
Neurodegenerative diseases
Neurosciences
Oligomers
Parkinson's disease
Parkinsons disease
Pathology
Physiology
Protein Binding
Protein Multimerization
Proteins
Proteolipid protein
Proteomics - methods
Quantitative analysis
Swine
Synapsin
Synaptosomes
Synaptosomes - chemistry
Synaptosomes - metabolism
Synuclein
Terminals
title Identification of synaptosomal proteins binding to monomeric and oligomeric α-synuclein
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