Ribosylation Rapidly Induces α-Synuclein to Form Highly Cytotoxic Molten Globules of Advanced Glycation End Products 英文参考文献.docVIP

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Ribosylation Rapidly Induces α-Synuclein to Form Highly Cytotoxic Molten Globules of Advanced Glycation End Products 英文参考文献.doc

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Ribosylation Rapidly Induces α-Synuclein to Form Highly Cytotoxic Molten Globules of Advanced Glycation End Products 英文参考文献

RibosylationRapidlyInducesa-SynucleintoFormHighly CytotoxicMoltenGlobulesofAdvancedGlycationEnd Products LanChen1.,YanWei1,3.,XueqingWang1,RongqiaoHe1,2,3* 1StateKeyLaboratoryofBrainandCognitiveSciences,InstituteofBiophysics,ChineseAcademyofSciences,Beijing,China,2LaboratoryofMentalHealth,Instituteof Psychology,ChineseAcademyofSciences,Beijing,China,3GraduateUniversityofChineseAcademyofSciences,Beijing,China Abstract Background: Alpha synuclein (a-Syn) is the main component of Lewy bodies which are associated with several neurodegenerativediseasessuchasParkinson’sdisease.WhiletheglycationwithD-glucosethatresultsina-Synmisfold andaggregationhasbeenstudied,theeffectsofglycationwithD-riboseona-Synhavenotbeeninvestigated. Methodology/Principal Findings: Here, we show that ribosylation induces a-Syn misfolding and generates advanced glycation endproducts (AGEs)which form proteinmolten globuleswith high cytotoxcity. Resultsfrom native- andSDS- PAGEshowedthatD-ribosereactedrapidlywitha-Syn,leadingtodimerizationandpolymerization.Trypsindigestionand sequencinganalysisrevealedthatduringribosylationthelysinylresidues(K58,K60,K80,K96,K97andK102)intheC-terminal regionreactedmorequicklywithD-ribosethanthoseoftheN-terminalregion.UsingWesternblotting,AGEsresultingfrom theglycationofa-Synwereobservedwithin24hinthepresenceofD-ribose,butwerenotobservedinthepresenceofD- glucose.Changesinfluorescenceat410nmdemonstratedagainthatAGEswereformedduringearlyribosylation.Changes in the secondary structure of ribosylated a-Syn were not clearly detected by CD spectrometry in studies on protein conformation.However,intrinsicfluorescenceat310nmdecreasedmarkedlyinthepresenceofD-ribose.Observationswith atomicforcemicroscopyshowedthatthesurfacemorphologyofglycateda-Synlookedlikeglobularaggregates.thioflavin T(ThT)fluorescenceincreasedduringa-Synincubationregardlessofribosylation.Asincubationtimeincreased,ribosylation ofa-Synresultedinablue-shift(,100nm)inthefluorescenceofANS.Thelightscatteringinten