帕金森病过去现在和未来2014

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tsofthediseasebasedongeneticmanipulations,buttheydonotprovideagoodmodeltovalidatenoveltherapeuticstrategiestobeusedinhuman.,Pathophysiology,41,conditionalPDanimalmodels,LeeY,DawsonVL,DawsonTM.AnimalmodelsofParkinsonsdisease:vertebrategenetics.ColdSpringHarbPerspectMed.2012;2.,Pathophysiology,AnimalmodelsofPD:Geneticmodels,42,AnimalmodelsofPD:Viralmodels,LeeY,DawsonVL,DawsonTM.AnimalmodelsofParkinsonsdisease:vertebrategenetics.ColdSpringHarbPerspectMed.2012;2.,Pathophysiology,43,AnimalmodelsofPD:Potentialroles,BlesaJ,PhaniS,Jackson-LewisV,PrzedborskiS.ClassicandnewanimalmodelsofParkinsonsdisease.JBiomedBiotechnol.2012;2012:845618.,Pathophysiology,44,Mitochondrialdysfunction,MPTP,Pathophysiology,PerierC,VilaM.MitochondrialbiologyandParkinsonsdisease.ColdSpringHarbPerspectMed.2012;2:a009332,45,Mitochondrialdysfunction,Pathophysiology,BenediktWestermann.Mitochondrialfusionandfissionincelllifeanddeath.NatureReviewsMolecularCellBiology11;872884.,Mitochondrialdynamics,46,Mitochondrialdysfunction,Pathophysiology,ExnerN,etal.MitochondrialdysfunctioninParkinsonsdisease.EMBOJ.2012;31:3038-3062.,PDgenesareimplicatedinvariousaspectsofmitochondrialbiology,47,Mitochondrialdysfunction,Pathophysiology,BenediktWestermann.Mitochondrialfusionandfissionincelllifeanddeath.NatureReviewsMolecularCellBiology11;872884.,48,Mitochondrialdysfunction,Pathophysiology,SugiuraA,McLellandGL,FonEA,51:43-55.,50,Mitochondrialdysfunction,Pathophysiology,Van,et.al.Theinterplayofneuronalmitochondrialdynamicsandbioenergetics:implicationsforParkinsonsdisease.NeurobiolDis.2013;51:43-55.,51,Mitochondrialdysfunction,Pathophysiology,SmithGA,etal.ThesearchforgeneticmousemodelsofprodromalParkinsonsdisease.ExpNeurol.2012;237:267-273.,Thecascadeofintracellulareventswhichleadtoearlyneuro-psychiatric,motorandolfactorydeficitsinprodromalPD,52,Mitochondrialdysfunction,Pathophysiology,ExnerN,etal.MitochondrialdysfunctioninParkinsonsdisease.EMBOJ.2012;31:3038-3062.,53,Oxidativestress,Pathophysiology,RuizS,etal.TargetingthetranscriptionfactorNrf2toameliorateoxidativestressandinflammationinchronickidneydisease.KidneyInt.2013;83:1029-1041.,Normally,over95%oftheoxygenconsumedinthebodyisconvertedtowaterbyacquisitionoftwoelectronsinasinglestep,54,Oxidativestress:Increasedoxidativedamage,Pathophysiology,SandersLH,etal.OxidativedamagetomacromoleculesinhumanParkinsondiseaseandtherotenonemodel.FreeRadicBiolMed.2013;62:111-120.WeinrebO,etal.TargetingdysregulationofbrainironhomeostasisinParkinsonsdiseasebyironchelators.FreeRadicBiolMed.2013;62:52-64.,Mitochondrialdysfunction,Dopamineoxidation,Ironincrease,Microgliaactivation,55,Oxidativestress:Decreasedantioxidantfunction,Pathophysiology,GlutathionemetabolisminPD,SmeyneM,SmeyneRJ.GlutathionemetabolismandParkinsonsdisease.FreeRadicBiolMed.2013;62:13-25.,Nrf2Signaling,Ironchelators,56,Oxidativestressandgene,Pathophysiology,VarcinM,etal.OxidativestressingeneticmousemodelsofParkinsonsdisease.OxidMedCellLongev.2012;2012:624925.,57,Alpha-synuclein:Thenativestate,Pathophysiology,HuangZ,et.al.Determiningnuclearlocalizationofalpha-synucleininmousebrains.Neuroscience.2011Dec29;199:318-32.,Pacificelectricray,Thenuclearlocalizationof-Synremainscontroversial,asconflictingresultshavebeenobtainedontheexistenceofendogenous-Synproteinsinnucleiofmammalianbrainneurons.Nuclearlocalizationof-Synhasbeenobservedintransgenicmiceexpressingamutantformof-Syn(A53T).Experimentsconductedinculturedprimaryneuronsandtransfectedmammaliancellshaveconsistentlydemonstratedthelocalizationof-Synproteinsinthenucleuswheretheymayacttoinhibithistoneacetylationandpromoteneurotoxicity,58,Alpha-synuclein;Thenativestate,Pathophysiology,VarcinM,etal.OxidativestressingeneticmousemodelsofParkinsonsdisease.OxidMedCellLongev.2012;2012:624925.,59,Alpha-synuclein:Thenativestate,Pathophysiology,SurprisinglyhighlevelsofSNCAinhumanredbloodcellsalthoughnooneknowswhy,ScherzerCR,etal.GATAtranscriptionfactorsdirectlyregulatetheParkinsonsdisease-linkedgenealpha-synuclein.ProcNatlAcadSciUSA.2008;105:10907-10912.,nonucleusnoDNAnoRNAnoproteinsynthesisnomitochondria,RBCs,AchaperoneAregulatorofmembranefluidityAnantioxidant,60,Alpha-synuclein:Thenativestate,Pathophysiology,LashuelHA,etal.Themanyfacesofalpha-synuclein:fromstructureandtoxicitytotherapeutictarget.NatRevNeurosci.2013;14:38-48.WittSN.Molecularchaperones,alpha-synuclein,andneurodegeneration.MolNeurobiol.2013;47:552-560.,Recombinanthuman-synpurifiedfromEscherichiacoliusingdenaturingconditionsisanintrinsicallyunfoldedmonomericprotein.andundercertainconditions,itslowlyformssolubleaggregatesandinsoluble-amyloidfibers.,Human-synpurifiedfromredbloodcells,orevenfromE.coli,usingnon-denaturingconditions,isnotamonomer.Instead,itisatetramerafour-helixbundlethatresistsaggregation.Tetrameric-synbindstophospholipidmembraneswithhigheraffinitythanmonomers,andthetetramersfailtoformfibersovera10-dayincubationperiod,whereasthemonomersdo.Thisraisesthepossibilitythatconditionsexistincellsthatbreakupthetetramers,therebyreleasingmonomersthatmayslowlyaggregateandfibrillize,61,Alpha-synuclein:Thenativestate,Pathophysiology,ThomasGurry,etal.TheDynamicStructureof-SynucleinMultimers.J.Am.Chem.Soc.,2013,135(10),pp38653872,TheDynamicStructureof-SynucleinMultimers,Althoughthereisdisagreementregardingwhetherthesolubleoligomericaggregatesorinsolubleaggregatesarethemostneurotoxicspecies,itisclearthat-synucleinself-associationplaysanintegralroleinneuronaldysfunctionanddeath.Theconformationallandscapeof-synucleinisnotoriouslydifficulttostudy,earningitthemonikerof“chameleon”duetoitstendencytoadoptdifferentconformationsunderdifferentexperimentalconditions.Thedominantstateofthisensembleisadisorderedmonomer,complementedbyasmallfractionofhelicaltrimersandtetramers.,62,Alpha-synuclein:Accumulationandaggregation,Pathophysiology,LashuelHA,OverkCR,OueslatiA,MasliahE.Themanyfacesofalpha-synuclein:fromstructureandtoxicitytotherapeutictarget.NatRevNeurosci.2013;14:38-48.,Accumulation,Aggregation,63,Alpha-synuclein:Accumulationandaggregation,Pathophysiology,LashuelHA,OverkCR,OueslatiA,MasliahE.Themanyfacesofalpha-synuclein:fromstructureandtoxicitytotherapeutictarget.NatRevNeurosci.2013;14:38-48.KaliaLV,etal.alpha-SynucleinoligomersandclinicalimplicationsforParkinsondisease.AnnNeurol.2013;73:155-169.,Theexistenceofvariousoligomericsynspeciesinvivounderpathophysiologicalconditions.Incontrasttofibrillarsyn,oligomericaggregatesaremostlikelytobelocatedinaxonsandpresynapticterminals,wheretheymightdamagesynapsesanddendrites.Thevariousoligomericspeciesseemtoexistinequilibriumwithmonomericsynandundergoaveryslowconversiontofibrilsintheabsenceofahighmolarratioofmonomerstootherspeciesofsyn.Therelationshipsbetweenthevarioussynoligomericspeciesandmechanismsoftheinter-conversionbetweenthesedifferentoligomersremainpoorlyunderstood.,anunfolded,extendedconformation,64,Alpha-synuclein:Accumulationandaggregation,Pathophysiology,LashuelHA,etal.Themanyfacesofalpha-synuclein:fromstructureandtoxicitytotherapeutictarget.NatRevNeurosci.2013;14:38-48.,Smaller-synucleinoligomers(sphericaloligomers26nmindiameter)aresuspectedofbeingmoretoxic.Theprocessoffibrilformation,ratherthanthefibrilsthemselves,hasanimportantroleinsyntoxicityandprogressiveneurodegenerationinPDandrelateddisordersToxicitymightberelatedtotheprocessofaggregationratherthanjusttothefinaloutcome(thatis,oligomersorfibrils),Underinvitroconditions,increasingproteinconcentrations,longincubationsat37C,additionofspecificmetalions(Fe2+,Cu2+andZn2+),nitrationorapplicationofvariousligands,suchasdopamine,caninducesynself-assembly.,Comparativelyreducedtoxicityformonomericsynisbasedontheuseofrecombinantproteinsinextracellulartoxicityassaysoronthecorrelationbetweenhighlevelsofsynoligomers.Twootherpossibilities:synoligomerizationmayalterthedistributionoffunctionalformsofmonomericsynorresultinmonomersequestrationintonon-functionaloligomericforms,thusresultinginpartiallossofsynfunction.ThenativeormisfoldedformsofthemonomericsynmayalsocontributetotoxicityandPDpathogenesisviaaggregation-independentmechanisms,includingaberrantinteractionswithmembranes,proteinsandsmallmolecules,retentioninspecificcellularcompartments,anddisruptionofspecificcellularprocesses.,Toxicityofmonomericsynuclein,65,Alpha-synuclein:Propagationandtransmission,Pathophysiology,PolymenidouM,etal.Prion-likespreadofproteinaggregatesinneurodegeneration.JExpMed.2012;209:889-893.PachecoC,etal.Anextracellularmechanismthatcanexplaintheneurotoxiceffectsofalpha-synucleinaggregatesinthebrain.FrontPhysiol.2012;3:297.,Prion-likespread,66,Alpha-synuclein:Propagationandtransmission,Pathophysiology,LashuelHA,etal.Themanyfacesofalpha-synuclein:fromstructureandtoxicitytotherapeutictarget.NatRevNeurosci.2013;14:38-48.PachecoC,etal.Anextracellularmechanismthatcanexplaintheneurotoxiceffectsofalpha-synucleinaggregatesinthebrain.FrontPhysiol.2012;3:297.,Prion-likespread,67,Alpha-synuclein:Propagationandtransmission,Pathophysiology,HansenC,etal.Beyondalpha-synucleintransfer:pathologypropagationinParkinsonsdisease.TrendsMolMed.2012;18:248-255.PachecoC,etal.Anextracellularmechanismthatcanexplaintheneurotoxiceffectsofalpha-synucleinaggregatesinthebrain.FrontPhysiol.2012;3:297.,Dual-hithypothesisofpropagationofsynucleinopathyduringPD,Braakstaging,68,Alpha-synuclein,Pathophysiology,ExnerN,etal.MitochondrialdysfunctioninParkinsonsdisease:molecularmechanismsandpathophysiologicalconsequences.EMBOJ.2012;31:3038-3062.,Relativeriskofneurodegeneration,Optimal,Low,High,Lossoffunction,Gainoffunction,69,Alpha-synuclein:Translocalization,Pathophysiology,PaulineWales1,etal.LimelightonAlpha-Synuclein:PathologicalandMechanisticImplicationsinNeurodegeneration.JournalofParkinsonsDisease3(2013)415459,70,Alpha-synuclein:Clearance,Pathophysiology,LashuelHA,OverkCR,OueslatiA,MasliahE.Themanyfacesofalpha-synuclein:fromstructureandtoxicitytotherapeutictarget.NatRevNeurosci.2013;14:38-48.,71,Alpha-synuclein:Clearance,Pathophysiology,Ebrahimi-FakhariD,etal.ProteindegradationpathwaysinParkinsonsdisease:curseorblessing.ActaNeuropathol.2012;124:153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