Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and Alzheimer's disease

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Review

Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and Alzheimer’s disease

Glyce´ralde´hyde-3-phosphate de´hydroge´nase (GAPDH) et la maladie d’Alzheimer N. El Kadmiri

^a,

*

^,c

, I. Slassi

^a,b

, B. El Moutawakil

^a,b

, S. Nadiﬁ

^a

, A. Tadevosyan

^e

, A. Hachem

^d

, A. Soukri

^c

aLaboratoryofMedicalGeneticsandMolecularPathology,FacultyofMedicineandPharmacy,HassanIIUniversity,Casablanca,Morocco

bDepartmentofNeurologyCHUIBNROCHD,Casablanca,Morocco

cLaboratoryofPhysiologyandMolecularGenetics,FacultyofSciencesAı¨nChock,HassanIIUniversity,Casablanca,Morocco

dLaboratoryofThrombosisandHemostasis,MontrealHeartInstitute,Montreal,Quebec,H1T1C8,Canada

eDepartmentofMedicine,Universite´ deMontre´al,Montre´al,Que´bec,H3C3J7,Canada

1. Introduction

Alzheimerdisease(AD)isasevereneurodegenerativedisease affecting the elderly and together with its related syndromes

(e.g. frontotemporal dementia, dementia associated with cere- brovascular disease and Lewy body dementia) are the leading causes of dementia [1]. Over a century ago, Alois Alzheimer described typical clinical characteristics, which are renowned neuropathological hallmarks of AD: progressive impairment of episodicmemoryandinstrumentalsigns,histologicalexamination of miliary bodies (senile plaques – composed of extracellular deposits of

b

-amyloid (A

b

)) and dense bundles of ﬁbrils PathologieBiologiexxx(2014)xxx–xxx

ARTICLE INFO

Articlehistory:

Received23June2014 Accepted29August2014 Availableonlinexxx

Keywords:

GAPDH

Alzheimer’sdisease b-amyloidaggregation Neuroﬁbrillarytangles

Motscle´s: GAPDH

Lamaladied’Alzheimer L’agre´gationdelab-amyloı¨de Encheveˆtrementsneuroﬁbrillaires

ABSTRACT

Glyceraldehyde-3-phosphatedehydrogenase(GAPDH)isaubiquitousenzymethatcatalyzesthesixth stepofglycolysisandthus,servestobreakdownglucoseforenergyproduction.Beyondthetraditional aerobicmetabolismofglucose,recentstudieshavehighlightedadditionalrolesplayedbyGAPDHinnon- metabolicprocesses,suchascontrolofgeneexpressionandredox post-translationalmodiﬁcations.

NeuroproteomicshaverevealedhighafﬁnityinteractionsbetweenGAPDHandAlzheimer’sdisease- associated proteins, includingtheb-amyloid, b-amyloid precursor proteinand tau. This neuronal proteininteractionmayleadtoimpairmentoftheGAPDHglycolyticfunctioninAlzheimer’sdiseaseand may be a forerunner of its participation in apoptosis. The present review examines the crucial implicationofGAPDHinneurodegenerativeprocessesandclariﬁesitsroleinapoptoticcelldeath.

ß2014PublishedbyElsevierMassonSAS.

RE´ SUME´

Laglyce´ralde´hyde-3-phosphatede´shydrogeńase(GAPDH)estuneenzymeubiquitairequicatalysela sixie`mee´tape de laglycolyseet serta` briserle glucosepourla productiond’eńergie. Au-dela` du me´tabolismeae´robietraditionnelduglucose,dese´tudesrećentesontmisene´videncelesroˆlesjoue´spar laGAPDHdans lesprocessusnon-me´taboliquestelsquelecontroˆlede l’expressiongeńique etles modificationspost-traductionnellesredox.Laneuroproteómiqueare´ve´le´ desinteractionsdehaute affinite´ entrelaGAPDHetlesproteínesassocieésa` lamaladied’Alzheimer,ycomprisleb-amyloı¨de, le prećurseur de b-amyloı¨deet la proteínetau. Son interactionavec des proteínes neuronalespeut conduirea` lapertedelafonctionglycolytiquedelaGAPDHdanslamaladied’Alzheimeretpeuteˆtreun prećurseurdesaparticipationdanslesprocessusapoptotiques.Lapre´senterevueexaminel’implication crucialedelaGAPDHdanslesprocessusneurode´geńe´ratifsetclarifiesonroˆledansl’apoptose.

ß2014Publie´ parElsevierMassonSAS.

* Correspondingauthor.

E-mailaddresses:elkadmiri1979@gmail.com,tresverre11@hotmail.com (N.ElKadmiri).

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PATBIO-3156;No.ofPages4

Pleasecitethisarticleinpressas:ElKadmiriN,etal.Glyceraldehyde-3-phosphatedehydrogenase(GAPDH)andAlzheimer’sdisease.

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(neurofibrillarytangles inside nerve cell bodies – composed of hyperphosphorylatedtau) [2–4]. Synapticloss,dendriticretrac- tion, neuronal progressive loss, dystrophic neuritis, granulova- cuolar degeneration, neuropil threads, Hirano bodies, and cerebrovascularamyloidarealsotypicalcharacteristicsthatare thought to have critical influence on cognitive and memory impairmentsobservedinADpatients[5–9].Atthistime,accurate earlydiagnosisof ADis problematicbecauseearlyneurological symptomsofrelentlessneurologicdeteriorationaresharedbya varietyofdisorders,anddefinitivediagnosisisonlypossiblebased onhistologicalinvestigationofthebrainatautopsy.

Analysisofthehumanproteomehasmadesignificantadvances andtherehasbeenagrowinginterestinapplyingproteomicsto researchclinicaldiagnosticsandpredictivetherapiesofneurode- generative disorders [10]. Identification and determination of proteins affecting the degree of neurodegeneration could con- tributetothedevelopmentofproteinbiomarkersthatarecritical fordiagnosingandmonitoringthediseaseanditsprogression,as well as predicting and monitoring the clinical benefits of the responsetotreatment.Inaddition,identificationofsuchproteins hasgreatlyfacilitated studiesatrevealingthemolecular events underlying neurodegenerative diseases. Research conducted in recentyearshasrevealedtheinvolvementoftheoxidoreductase, glyceraldehyde-3-phosphate dehydrogenase (GAPDH), in AD pathology[11–13].Geneticsandneuroproteomicshaverevealed highaffinityinteractionsbetweenGAPDHandneurodegenerative disease-associated proteins, including the

b

-amyloid (A

b

)pre- cursorprotein(A

b

PP),A

b

andneurofibrillarytangles.GAPDHis subjecttoseveralformsofoxidativemodificationsinbrainsofAD patients,whichfundamentallydisturbitschemicalstructureand biologicalfunction,includingS-glutathionylation,S-nitrosylation, anditsreactionwithreactiveoxygenspecies(ROS)[14–17].Here, we review the essential role of GAPDH in Alzheimer’s disease pathology;weparticularlyfocus on itsstructural modifications thatinduceamyloidandtauproteinsaggregation.

2. GAPDHstructureandfunction

GAPDH enzymes are a family of largely expressed oxidor- eductases known for their key role in glycolysis. In glucose metabolism,it is catalyzing the phosphorylation of glyceraldehyde-3-phosphate(G3P) to1,3-bisphosphoglycerateusingnico- tinamideadeninedinucleotide(NAD⁺)asacofactor.Itprovidesthe biologicalstartingpointnotonlyfortheglycolyticsynthesisofATP but also for reducing equivalents accessible for oxidative phosphorylation. GAPDH exists as a homologous tetramer (148kDa),dimer(74kDa)andmonomer(37kDa)[18].Each GAPDH monomeric form consists of two conserved binding domains:anN-terminalNAD⁺-bindingdomainandaC-terminal catalytic,orG3P-bindingdomain[19].Ingeneral,GAPDHisusedas ahousekeepinggene,orcytosoliccontrolmarkerinproteinand geneexpressionstudies,aswellasareferenceloadingcontrolin routinebiochemical analysis (e.g. Northern and Westernblots) becauseofitssequencepreservationandexpressionacrossspecies [20].However,recentexperimentalevidencesuggestthatbeyond glycolyticfunctions,GAPDHisinrealityamultifunctionalprotein thathasbeenreportedto:bindnucleicacids[21,22],regulategene expression/transcription[23],possesskinase/phosphotransferase activity[24],facilitatevesiculartransport[25],andbindintegral membraneionpumpsassociatedwithcellCa²⁺release[26],aswell as interact with a number of small key molecules, including ribozymes[27],glutathione(GSH)[28],p53[29],andnitricoxide (NO) [30–33]. Moreover, GAPDH also interacts and form com- plexes with neurodegenerative disease-related proteins, like huntingtin [33,34],

b

-amyloid and the

b

-amyloid precursor

protein (A

b

PP) [35–38]. Hence, GAPDH cellular manifestations independentofitsroleinenergyproductionisofgreatimportance to neurodegenerativedisease research, speciﬁcallyin brains of subjectswith ADbecause formationof

b

-APP or

b

-AP–GAPDH protein complexescouldresult in a reduced level of glycolysis andthusofglucoseconsumption.

3. GAPDHand

b

-amyloid/

b

-amyloidprecursorprotein aggregation

Asindicated,recentstudiesrevealedthespeciﬁcinteractionof GAPDHwithneurodegenerativediseaseproteins andthis could potentiallycorrelatewithpathologicalfeatures.Initialinvestiga- tions into the involvement of GAPDH in AD reported cross- reactivity between GAPDHand themonoclonal antibodyAm-3, which recognizes parent A

b

PP but not cleaved A

b

, in brain specimensfromADpatients[12].Tamaokaetal.suggestedthat suchcross-reactivitywasunlikelyascribedtohomologiesbetween epitopesinvolving similar post-translationalmodiﬁcation,since their putative sites arepresumed to lie outside theA

b

(1–42) sequenceregioninA

b

PP,butweremostlikelyduetoconforma- tional similarities between A

b

and GAPDH, which would ultimately complicate the immunochemical and immunocyto- chemicaldetectionofAD[39,40].Furthermore,adirectinteraction betweenGAPDHandA

b

PPhasbeenobservedbygelﬁltrationby Schulzeetal.,inwhichbrainmonomericGAPDHinteractedwith thecytoplasmicC-terminaldomainofrecombinantA

b

PP,while maintaining the rate of glycolysis [15]. Subsequent studies established that brain-derived GAPDH could bind a variety of A

b

isoforms,exhibitinggreatestafﬁnityforA

b

(1–42)[41–43].

Recently, antibodies that reveal Alzheimer’s diseaseplaques were shown to also interact with nuclear GAPDH from post- mortemspecimensobtainedfromADsubjectsandfromcultured cells incurring apoptosis. Mazzola et al. reported decreased intracellularglycolytic activityofGAPDH inAD patients,which was27%lessglycolyticallyactiveinAlzheimer’scellsascompared with age-matched controls, in both nuclear and post-nuclear fractions [44]. These results provided critical evidence that inhibition of GAPDH’senzymatic activityin AD cells is due to post-translationalalterationsoftheGAPDHproteinstructureand witnessedthatsubcellularfractionationanalysismaybevitalto understanding GAPDH’s cellular function in neurodegenerative diseases.

As mentioned earlier, GAPDH can undergo many different oxidative post-translational modiﬁcations, which inﬂuence its chemical structureand biological activity,andare abletoform highlystablecomplexeswithsolubleA

b

toformaggregates.Active site modiﬁcations consist of mono-ADP-ribosylation, GAPDH- transition metal complex formation, S-glutathionylation and S-nitrosylation by NO or other reactive nitrogen species [45,46]. In brains of AD individuals, such oxidative protein modiﬁcations are common, as several groups reported the relationship between oxidative stress and damage as a major hallmarkofADpathology,precipitatinglossofneurons,synapses, andinthelongrun,normalbrainfunction.Cummingetal.revealed thatA

b

promotesanincreaseinGAPDHintermoleculardisulﬁde bonding in all examined brain extractsfromAD individuals as comparedwithage-matchedcontrols[36].Infactintheirstudy, A

b

treatmentofprimaryandimmortalizedneuronsresultedinthe lossofa120kDadisulﬁde-linkedisoformofGAPDHinthecytosol andconcomitantappearanceofthesameisoforminthenucleus, suggestingthatoxidativestressinducedbyA

b

promotesnuclear accumulationofdisulﬁde-bondedGAPDH.Inaddition,A

b

treat- mentincreasestheintracellularconcentrationofROSincultured nervecells.Disulﬁde-linkedinsolubleaggregatesofhighmolecular weight GAPDH found in AD patients, and aged transgenic AD N.ElKadmirietal./PathologieBiologiexxx(2014)xxx–xxx

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PatholBiol(Paris)(2014),http://dx.doi.org/10.1016/j.patbio.2014.08.002

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micemayincreasecytotoxicityand indirectlytrigger apoptosis.

Moreover,treatmentofHT22cellswithH2O2ordiamidemimicked theformationofhighmolecularweightdisulfide-linkedGAPDH multimers and resulted in a reduction of about 94% and 66%, respectively, of the GAPDH glycolytic activity as compared to untreated cells. To investigated themolecular mechanism that underliesoxidativestress-triggeredaggregationofGAPDHandthe relationshipbetweenstructuralabnormalitiesinGAPDHandcell death, Nakajima et al., prepared cysteine-substituted mutants C149S, C153S, C244A, C281S, and C149S/C281S of GAPDH to identify residues responsible for disulfide-linked aggregates formation [47]. Their results revealed that neither C149S nor C149S/C281Smutantsaggregated,proposingthattheactivesite cysteine of GAPDH plays an essential role in amyloid binding, aggregationandpromotionofcelldeath.Hence,post-translational modificationsof theredox-sensitiveglycolytic enzyme,GAPDH, inducesamyloid-likeaggregationthroughalterationinGAPDH’s conformation via formation of aberrant disulfide bonds at the active site at cysteine 149, which leads to the formation of insolubleaggregatestherebypromotingneuronalapoptosis.

4. GAPDHandtauaggregation

Neuroﬁbrillarytangles(NFTs)areintraneuronallesionsformed by hyperphosphorylation of themicrotubule-associated protein tauthatleadstoinsolubleneurotoxicaggregates,ofwhich,paired helicalﬁlaments(PHF)-tauareamajorcomponent.Generally,tau binds tomicrotubulesandis essential foraxonaltransport and maintenanceoftheneuronalnetwork.Neurodegenerative tauo- pathiessuggestthattheabnormalhyperphosphorylationofthetau protein results in a loss of its function, which leads to depolymerizationofmicrotubules,formationofneurotoxicNFTs anddisturbedaxonaltransport,followedbyneuronaldysfunction andneurodegeneration[48–50].TheexplicitrelationbetweenA

b

deposition and tau-related pathology is not clear yet, but tau aggregationhasmanyconsequencesonneuronsandisprobably theﬁnalcommoncauseofneurodegenerationinAD.LC-MS/MS analysis conﬁrmed that GAPDH co-localized with NFTs and immunoprecipitated with PHF-tau in specimens from the temporalcortexofbrainsfromADpatients[51,52].Furtherstudies by Chenet al. provided evidencethat tau wasable tointeract andinducethedenaturationandinactivationofGAPDH.Authors havealsoestablishedthatthephosphorylatedandpre-aggregated PHF-tau was unable to bind or affect GAPDH denaturation or activity, suggesting a direct involvement of GAPDH in tau aggregationandNFTformationinADpatients’brains.

5. Conclusion

Considerableprogressin thesearchofa novel ADbiological biomarkerhasbeenmadewithmarkersderivedfrompathological lesions.Todate,themostpromisingsourcesofbiomarkersinAD werecerebrospinalﬂuid(CSF)andbloodplasma,becauseoftheir accessibility.Severalbiomarkershavebeensuggestedsuchasthe CSFtotal-tau[53],phospho-taulevelsandCSFA

b

(1–42)levels [54,55]. The identiﬁcation of proteins affecting the degree of neurodegenerationcouldenormouslycontributetothedevelop- mentofbiomarkersandmaybeexploredfortheirvalueasanew drugtargetsinAD.Thestrongevidenceoftheinteractionbetween GAPDHandA

b

PP,A

b

,andtaudemonstratesitsdirectparticipa- tionintheaggregationofthesethreeproteinsintotheirinsoluble counterparts. Although the precise molecular mechanisms of manyoftheGAPDHinteractionsandprocessesdescribedinthis review arenot yet clear,thestructure, activityand subcellular localization of GAPDH remains crucial for understanding the countlessrolesitplaysinnormalandneuropathologicalcellular

functions. Therefore, these ﬁndings open new avenues for diagnosis by using GAPDH as a biomarker and a promising therapeutictargettosloworcureneurodegenerationinbrainsof ADpatients.

Disclosureofinterest

The authors declare that they have no conﬂicts of interest concerningthisarticle.

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