Page - 53 - in Advances in Neuroimmunology

BrainSci. 2016,6, 41 comprised predominantly ofα-synuclein (α-syn). These protein aggregates have been observed throughout thebrain,andpathologicalα-syndeposition is thought tobegin in themedullaandspread throughout themidbrain to cortical regions in amanner that corresponds to the onset of clinical symptoms[2]. Theseproteinaggregatesareassociatedwithmicrogliosis [3], and impairedcellular physiology,althoughtheprecisemechanisms leadingtocytotoxicityarecurrentlyunknown. ThevastmajorityofParkinson’sdiseasecasesareclassifiedas idiopathic,butapproximately5% ofPDcasesaregenetically linked. Thereareseveralgenemutations thatconfersusceptibilityorare associatedwith thedevelopmentofPD, includingmutations in leucine-richrepeatkinase2 (LRRK), PTENInducedputativekinase1(PINK1),andtheproteindeglycase(DJ1).However,α-synhasproven tohaveavery strongassociationandrelevance toPDandsimilardisorders collectivelyknownas synucleinopathies. Abnormalities in the SNCAgene that encodes theα-syn protein are strongly correlatedwith thedevelopmentofanautosomaldominant familial formofPD[4].Multiplicationsof theSNCAgeneareknownto increase theexpressionof theα-synprotein,whereascertainmissense mutations of the gene (A53T,A30P, E46K)produce variants ofα-syn, both ofwhichhave known pathologicalattributes relatedto the increasedpropensity toaggregate. The physiological role of α-syn, along with the isoforms β- and γ-synuclein, is related to neurotransmission,andtheyareprimarily locatedinthesynapse. Increasedconcentrationsofα-syn proteinormutatedformsofα-synmaketheproteinsusceptible tomisfoldingandpolymerizationby self-assembly. Thesemisfoldedaggregateshaveheterogeneousconformationsthathavenotbeenclearly elucidated. Theseaggregatesareassociatedwithvariousdeleteriousbiologicalactivities including(1) thepermeabilizationof thecellularmembranes [5], associatedwithanalterationof intracellular ion concentrations [6]; (2)disruptionofenergyproductionthroughinteractionswith themitochondria [7]; and (3) interruptionof intracellular transport viaphysical interference ofmotorproteins, or direct interactionwithorganellesandvesicles [8]. Theformationofsolubleoligomericspecies ispresumed to be relativelymore toxic than fibrils, through the energetically favorable associationwithin the phospholipids that formspores in thecellularmembrane[9]. TheamountofLBformations throughout thebrainreflects theseverityof impairment [10].However, ithasbeenpostulatedthat theorganizing offibrils intoLewyBodiesmayserveasaprotectivemechanismtodivert toxicaggregatespecies into lessharmful formations topreservenormalcellularphysiology[11]. 2.TheInteractionwithAging Aging is amajor risk factor for the development of PD [12], evidenced by the fact that the incidence increases foreverydecadeover50yearsofage. Whileagingcontributes toPD, it is also underrepresented inPDresearch,as it is commonfor theexperimentalmodels tobecarriedoutusing younganimals.However, the impactofaging isessential toconsider in termsof thediseaseprocess becausemanyof thephysiological changes thatoccur inagedanimals candriveor exacerbate the pathologicalmechanismsthat leadtoPDandalterboth thecourseandtempoof thedisease. The impactof agingon the incidenceofPDis compoundedby the fact that thedopaminergic neuronsoftheSNseemtohaveauniquevulnerabilitytocellularstressorsinthemicroenvironment[12]. Althoughit isnotcompletelyunderstoodwhatsets thesecellsapart fromthoseofotherDApathways, the neurons of this nucleus aremore susceptible to the homeostatic disturbances anddegenerate significantlymorecomparedtosimilaroradjacent regions [13]. Thiscanbegrosslyattributedtohigh oxidativestressand inflammation. It isknownthat theSNisexposed tohigher levelsofoxidation comparedtootherdopaminergiccenters [11]. This ispartlyduetoanunusuallyhighconcentrationof iron,which through theFentonreaction, cangenerate free radicals, aswell asnitricoxide released bymicroglia thatdenselypopulate this region [14,15]. In addition to theaccumulationof reactive oxygenandnitrogenspecies, theSNisalso ill-equippedtoneutralize them,duetoa lowexpression ofglutathione,an importantendogenousantioxidantmolecule, leadingtoaninevitable increase in oxidative stress [16]. Aging is also associatedwith increased levels of oxidative stress andaltered 53