Alphasynucleinisamemberofthesynucleinfamily,theothertwoproteinsbeingbetaandgammasynuclein.AlphasynucleinwasoriginallyisolatedasamajorsynapticvesicleassociatedproteinfromtheelectricorganofthefishTorpedo(1).Directhomologuesofalpha-synucleinarefoundinallvertebrates.Laterworkconnectedalpha-synucleinwithhumanbrainpathology,whenaproteinoriginallyidentifiedasacomponentofNAC,the"Non-AmyloidbetaComponentofAlzheimer"sdiseaseamyloid"provedtobeapeptidederivedfromalpha-synuclein(2).
Image:Mixedneuron-glialculturesstainedwithalpha-synuclein (red)andchickenpolylclonalantibodytoMAP2 (green).Thealpha-synucleinantibodystainsvesicularstructurestheperikaryaandprocessesoftheneuronsinthis Notethatsomeoftheneuronalperikaryacontainmuchmorealpha-synucleinthanothers.ThebluechannelshowsthelocalizationofDNA. Inset:Blotsofantibodyagainst recombinantalpha-synuclein(leftlane)andcrudeextractofmousebrain(rightlane).ProtocolonData-sheet.
Thealpha-synucleinproteinisthereforesometimesknownasNACprecursororNACP.Furtherworkshowedthatalpha-synucleinisamajorcomponentoftheLewybodiesofParkinson"sdiseaseandpointmutationsofalpha-synucleinprovedtobecausativeofsomeformsoffamilialParkinson"sdisease(3,4,5).However,despitebeingdiscoveredasascomponentofamyloidpreparations,alpha-synucleinisapparentlynotamajorcomponentofthesenileplaquesofAlzheimer"sdisease(6).EarlyonsetParkinson"sdiseasemaybecausedbyaduplicationortriplicationofoneofthealphasynucleingenes(7,8).Alpha-synucleinisalsofoundintheLewybodiesofpatientswithdiffuseLewybodydiseaseandinclusionsinglialcellsinthebrainsofpatientswithmultiplesystematrophy(MSA)andamyotrophiclateralsclerosis(ALS).Alpha-synucleinisheavilyexpressedinbrainandappearstobelocalizedprimarilytopresynapticregions,thoughnotwithatypicalsynapticvesicledistributionpattern.Thesynucleinproteinsappeartohavelittle3Dstructureinsolution,andprobablybelongtothefamilyof"intrinsicallyunstructuredproteins"whichonlyadoptawell-definedconformationwhenboundtootherproteinsormembranelipids(9).Anexcellentrecentreviewoftheroleofalpha-synucleininhealthanddiseasewasrecentlypublishedbyMarkCookson(10).
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