Omic Studies of Neurodegenerative Disease - Part B, PDF
Preview Omic Studies of Neurodegenerative Disease - Part B,
INTERNATIONAL REVIEW OF NEUROBIOLOGY VOLUME122 SERIES EDITORS R. ADRON HARRIS WaggonerCenterforAlcohol andDrugAddictionResearch The University of Texas at Austin Austin, Texas, USA PETER JENNER Division of Pharmacology and Therapeutics GKT School of Biomedical Sciences King's College, London, UK EDITORIAL BOARD ERICAAMODT HUDAAKIL PHILIPPEASCHER MATTHEWJ.DURING DONARDS.DWYER DAVIDFINK MARTINGIURFA BARRYHALLIWELL PAULGREENGARD JONKAAS NOBUHATTORI LEAHKRUBITZER DARCYKELLEY KEVINMCNAUGHT BEAULOTTO JOSE(cid:1)A.OBESO MICAELAMORELLI CATHYJ.PRICE JUDITHPRATT SOLOMONH.SNYDER EVANSNYDER STEPHENG.WAXMAN JOHNWADDINGTON AcademicPressisanimprintofElsevier 125LondonWall,London,EC2Y5AS,UK 525BStreet,Suite1800,SanDiego,CA92101-4495,USA 225WymanStreet,Waltham,MA02451,USA TheBoulevard,LangfordLane,Kidlington,OxfordOX51GB,UK Firstedition2015 ©2015ElsevierInc.Allrightsreserved. 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ISBN:978-0-12-804762-0 ISSN:0074-7742 ForinformationonallAcademicPresspublications visitourwebsiteathttp://store.elsevier.com/ CONTRIBUTORS NimishK.Acharya BiomarkerDiscoveryCenter,NewJerseyInstituteforSuccessfulAging,andDepartmentof GeriatricsandGerontology,RowanUniversitySchoolofOsteopathicMedicine,Stratford, NewJersey,USA VictoriaAyala DepartmentofExperimentalMedicine,UniversityofLleida-BiomedicalResearchInstitute ofLleida,Lleida,Spain AlejandroBotas BioSciencesDepartment,RiceUniversity,Houston,Texas,USA RosannaCabre´ DepartmentofExperimentalMedicine,UniversityofLleida-BiomedicalResearchInstitute ofLleida,Lleida,Spain HannahMooreCampbell MedicalScientistTrainingProgram,BaylorCollegeofMedicine,Houston,Texas,USA AlejandroCifuentes LaboratoryofFoodomics,InstituteofFoodScienceResearch(CIAL),CSIC,Madrid,Spain CassandraDeMarshall BiomarkerDiscoveryCenter,NewJerseyInstituteforSuccessfulAging;GraduateSchoolof BiomedicalSciences,RowanUniversity,andDepartmentofGeriatricsandGerontology, RowanUniversitySchoolofOsteopathicMedicine,Stratford,NewJersey,USA IsidreFerrer InstituteofNeuropathology,BellvitgeUniversityHospital,UniversityofBarcelona, BiomedicalResearchInstituteofBellvitge,L’HospitaletdeLlobregat,Barcelona,andCenter forBiomedicalResearchonNeurodegenerativeDiseases(CIBERNED),ISCIII,Madrid, Spain GeorgeGodsey GraduateSchoolofBiomedicalSciences,RowanUniversity,andDepartmentofGeriatrics andGerontology,RowanUniversitySchoolofOsteopathicMedicine,Stratford,New Jersey,USA EricGoldwaser BiomarkerDiscoveryCenter,NewJerseyInstituteforSuccessfulAging;GraduateSchoolof BiomedicalSciences,RowanUniversity,andDepartmentofGeriatricsandGerontology, RowanUniversitySchoolofOsteopathicMedicine,Stratford,NewJersey,USA HugoGonzalo DepartmentofExperimentalMedicine,UniversityofLleida-BiomedicalResearchInstitute ofLleida,Lleida,Spain vii viii Contributors XuHan DepartmentofPediatrics,BaylorCollegeofMedicine,andJanandDanDuncan NeurologicalResearchInstituteatTexasChildren’sHospital,Houston,Texas,USA ClaraIba´n˜ez LaboratoryofFoodomics,InstituteofFoodScienceResearch(CIAL),CSIC,Madrid,Spain MarionaJove´ DepartmentofExperimentalMedicine,UniversityofLleida-BiomedicalResearchInstitute ofLleida,Lleida,Spain MirjanaMaletic-Savatic DepartmentofPediatrics;JanandDanDuncanNeurologicalResearchInstituteatTexas Children’sHospital;PrograminDevelopmentalBiology;PrograminStructuraland ComputationalBiologyandMolecularBiophysics,andDepartmentofNeuroscience,Baylor CollegeofMedicine,Houston,Texas,USA EricP.Nagele BiomarkerDiscoveryCenter,NewJerseyInstituteforSuccessfulAging,RowanUniversity SchoolofOsteopathicMedicine,Stratford,andDurinTechnologies,Inc.,NewBrunswick, NewJersey,USA RobertG.Nagele BiomarkerDiscoveryCenter,NewJerseyInstituteforSuccessfulAging;Departmentof GeriatricsandGerontology,RowanUniversitySchoolofOsteopathicMedicine,andDurin Technologies,Inc.,NewBrunswick,NewJersey,USA AlbaNaud´ı DepartmentofExperimentalMedicine,UniversityofLleida-BiomedicalResearchInstitute ofLleida,Lleida,Spain ReinaldPamplona DepartmentofExperimentalMedicine,UniversityofLleida-BiomedicalResearchInstitute ofLleida,Lleida,Spain ManuelPortero-Ot´ın DepartmentofExperimentalMedicine,UniversityofLleida-BiomedicalResearchInstitute ofLleida,Lleida,Spain MarioRango DepartmentofNeurologicalSciencesandExcellenceCenterforadvancedMRstudies, IRCCSCa’Granda-OspedaleMaggiorePoliclinicoFoundation,UniversityofMilan, Milano,Italy AbhirupSarkar BiomarkerDiscoveryCenter,NewJerseyInstituteforSuccessfulAging;GraduateSchoolof BiomedicalSciences,RowanUniversity,andDepartmentofGeriatricsandGerontology, RowanUniversitySchoolofOsteopathicMedicine,Stratford,NewJersey,USA CarolinaSimo´ LaboratoryofFoodomics,InstituteofFoodScienceResearch(CIAL),CSIC,Madrid,Spain PREFACE Ifyoucanpasstheanathematicword“omic”andchoosetoreadthisvolume oftheInternationalReviewofNeurobiology,thenyouwillhavedoneyourselfa favor.Becausenestledwithintheusualscientificproseissometrulyoutstand- ing and innovative work describing state-of-the-art omic investigations into the cause, diagnosis, and treatment of neurodegenerative disorders such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis, multiple sclerosis, and prion diseases. The aim of the volume is to bring together diverse work that explores facetsofneurodegenerativediseasethatareoften overlookedby traditional hypothesis-driven research and to present such work in a readable format which appeals to researchers and students from a wide range of scientific backgrounds. The reason for doing so is that neurodegenerative diseases ruin and fre- quentlyshortenthelifeofthepatientandplaceimmensestrainupontheirfam- ilies and carers of the affected individual. This in turn has a high social and economic cost to society as a whole. Paradoxically, as advances in medicine successfully treat many illnessesand lifeexpectancy increases, theprevalence of neurodegenerative disease is also rising, since the biggest risk factor for the most common neurodegenerative diseases is aging. Consequently, these costswillonlygetworseastheworldpopulationagesandtheapparentadvan- tagesofagreaterlifeexpectancyarelessdesirableiftherealityisthatthereisa highprobabilityofdevelopingadebilitatingdiseasewhichrenderstheindivid- ualdependentonconstantcare.Yet,despitethevastquantitiesofresearchthat hasbeenconductedovermanydecadesintoneurodegenerativediseases,inthe majorityofcasesthecauseofneurodegenerationisunknownandtreatments,if available,onlytacklesomesymptomsofneurodegenerationanddonothingto slowtheprogressionofthedisease. The chapters in this volume of International Review of Neurobiology show- case novel approaches to study the genome, proteome, and metabolome of samples from patientswith neurodegenerative diseasein thehope offinding cluesregardingthecausesofneurodegenerativedisease,furtheringourunder- standing of mechanisms of neurodegeneration, aiding earlier diagnosis throughthedetectionofbiomarkers,andidentifyingputativetherapeutictar- getsthatwillallowsuccessfultreatmentofneurodegenerativediseasesordelay their onset. ix x Preface Finally,Iwouldliketothanktheauthorsofthechaptersinthisvolume fortheirworkandhopethatthereadersfindsomethingwithinthevolume that stimulates them to contribute toward further research into the cause, treatment, and cure of neurodegenerative disease in the future. MICHAEL J. HURLEY London, April 2015 CHAPTER ONE Utility of Autoantibodies as Biomarkers for Diagnosis and Staging of Neurodegenerative Diseases Cassandra DeMarshall*,†,{, Abhirup Sarkar*,†,{, Eric P. Nagele*,}, Eric Goldwaser*,†,{, George Godsey†,{, Nimish K. Acharya*,{, Robert G. Nagele*,{,},1 *BiomarkerDiscoveryCenter,NewJerseyInstituteforSuccessfulAging,RowanUniversitySchool ofOsteopathicMedicine,Stratford,NewJersey,USA †GraduateSchoolofBiomedicalSciences,RowanUniversity,Stratford,NewJersey,USA {DepartmentofGeriatricsandGerontology,RowanUniversitySchoolofOsteopathicMedicine, Stratford,NewJersey,USA }DurinTechnologies,Inc.,NewBrunswick,NewJersey,USA 1Correspondingauthor:e-mailaddress:[email protected] Contents 1. Introduction:ABriefHistoryofAutoantibodies 3 2. ACausalRoleforAutoantibodiesRevealedinWell-KnownAutoimmuneDiseases 4 2.1 RoleofAutoantibodiesandProteinCitrullinationinRheumatoidArthritis 4 2.2 SLE,anAutoimmuneDiseasewithAutoantibodiesDirectedAgainstCommon NuclearandCytoplasmicProteins 5 2.3 SystemicSclerosis(Scleroderma) 7 3. AutoantibodiesinCancer:ByproductorBiomarker? 8 4. EscalatingInvolvementofAutoantibodiesinNeurologicalandNeurocognitive Disorders 9 4.1 Introduction 9 4.2 MG—AClassicalExampleofAutoantibodiesCausingaNeurologicalDisease 11 4.3 MS—ANeuroinflammatoryDemyelinatingDiseaseAssociatedwith Autoantibodies 13 4.4 NeuromyelitisOptica—ANeuroinflammatoryDemyelinatingDiseasewitha CausativeAutoantibody 15 4.5 Anti-NMDAREncephalitis—AutoantibodiesTargetingReceptorsCausing NeuropsychiatricSymptoms 16 4.6 AD—EvidencethatAutoantibodiesandBlood–BrainBarrierBreakdownAre PartnersinCrime 18 InternationalReviewofNeurobiology,Volume122 #2015ElsevierInc. 1 ISSN0074-7742 Allrightsreserved. http://dx.doi.org/10.1016/bs.irn.2015.05.005 2 CassandraDeMarshalletal. 5. Autoantibodies:Abundant,Ubiquitous,andClinicallyUseful 19 5.1 TheRiseofNaturalAutoantibodies 19 5.2 PrevalenceandStabilityofNaturalAutoantibodies 21 5.3 IsotypeandReactivityofNaturalAutoantibodies 21 5.4 NaturalAutoantibodyProduction 22 5.5 FunctionofNaturalAutoantibodies 23 5.6 ImplicationsandOpportunity 24 6. MethodsofAutoantibodyDetectioninBiofluids 24 6.1 ProteomicApproachesforAutoantibodyAnalysisinBiologicalSamples 24 6.2 DiscoveryofCandidateAutoantibodyBiomarkersUsingtheWholeHuman Proteome 26 6.3 AutoantibodyDiscoverybyFluid-PhaseImmunoassays 27 6.4 AutoantibodyDiscoverybyAntigenMicroarrayTechnologies 27 6.5 ValidationofBiomarkerCandidates 29 7. UtilityofAutoantibodiesasBiomarkersofDisease 29 7.1 ClassicalTargetsMisstheMarkastheMostUsefulDiagnosticBiomarkers 30 7.2 Immunoglobulin-BindingPatternsUsingRandomPeptideLigandsand MimeticsforBiomarkerIdentificationinAD 32 7.3 Disease-SpecificAutoantibodyProfilesUsingHumanProteinMicroarraysfor theDiagnosisandStagingofADandPD 33 8. ConclusionsandPerspectives 35 Acknowledgments 37 References 37 Abstract Autoantibodiesareself-reactiveantibodiesthathavebeenwidelyimplicatedascausal agentsofautoimmunediseases.Theyarefoundinthebloodofallhumansera,regard- lessofage,gender,orthepresenceorabsenceofdisease.Whiletheunderlyingreason fortheirubiquityremainsunknown,ithasbeenhypothesizedthattheyparticipatein theclearanceofblood-bornecellandtissuedebrisgeneratedinbothhealthyanddis- easedindividualsonadailybasis.Althoughmuchevidencesupportsthisdebrisclear- ancerole,recentstudiesalsosuggestacausalroleforautoantibodiesindisease.This chapter first presents well-known examples of autoimmune diseases that emphasize adirectcausalroleforautoantibodiesandthendiscussestheveritableexplosionofevi- dencenowsupportingtheirinvolvementinawidevarietyofotherdiseases,including cancersandseveraltypesofneurologicalandneurodegenerativediseases.Lastly,trans- lational strategies that take advantage of the “cause and/or effect” role of autoanti- bodies and recent technological advancements in their detection to exploit autoantibodiesassensitiveandspecificbiomarkersusefulforthedetectionanddiag- nosisofdiseaseareoutlined.TheiruseinthediagnosisandstagingofAlzheimer'sand Parkinson'sdiseasesispresented,andfutureapplicationsinclinicalmedicineandbasic sciencearehighlighted. AutoantibodiesasBiomarkersofDisease 3 1. INTRODUCTION: A BRIEF HISTORY OF AUTOANTIBODIES Autoantibodies, in the most basic conception, are simply antibodies thatbindtoone’sself.Thefactthattheyevenexisthasbeensubjecttonearly a century of ardent opinion and unanticipated discovery. Earlypioneersofimmunologyleftnoroomfortheexistenceofautoan- tibodies.PaulEhrlich,afatherofthemodernhumoralimmunesystem,was openly antagonistic to the idea. He envisioned that individuals have the capacitytoproduceantibodiestoeverypossiblenonself-antigenuponexpo- sureandthatthiswasaprimarymechanismoffightingdiseaseandinvasion (Ehrlich, 1899). The lynchpin of this theory, however, was that one could neverproduceantibodiestoone’sself—todothiswouldunleashacataclysm of immune self-destruction. Organisms therefore must have a tolerance to themselves and an aversion to self-recognition, the horror autotoxicus. Succeeding decades proved more technical in their elaboration of this concept. Sir Frank Macfarlane Burnet provided a tentative mechanism for absolute self-tolerance in his clonal selection theory of acquired immunity (Burnet,1959).There,hesuggestedthatBlymphocyteswithsurfacerecep- torsrespondingtoforeignantigenswouldbeselectivelystimulatedtoclon- ally proliferate and thereby increase the capacity for production of a single protectiveantibody.Ontheotherhand,anyBcellthatrespondedtoaself- antigenduringfetallifewouldbeselectively“deleted,”andthustheability to produce antibodies that recognize and bind to one’s selfwould be erad- icated forever. But the twentieth century was marked by the discovery of dozens of autoimmune diseases clearly mediated by antibodies binding to self. The dogmaofstrictself-toleranceeventuallycrumpledundertheweightofclin- icalevidence.Autoantibodiesnowseemedtobereal.Despitethisrelatively recentadmission,ithadbeenknownthatantibodiesreactwithself-antigens on spermatozoaand erythrocytes for over a century(Avrameas,Ternynck, Tsonis, & Lymberi, 2007). And there had been convincing evidence of autoantibodies and their relationship with disease as early as 1904 (Donath & Landsteiner, 1904). The existence of autoantibodies was finally accepted,buthadtobereconciledwithinthepreviousframeworkofimmu- nologicalthinking.Itwaspostulatedthatonlyaconditionofgrossimmune 4 CassandraDeMarshalletal. dysregulationwouldallowfortheirproduction,andthatiswhatwenowcall an autoimmune disease. In this paradigm, the presence of autoantibodies always indicates disease and so they are biomarkers by their very nature. Thepastthreedecadeshaverevealedmuchabouttheprevalenceofauto- antibodies.Itisnowexceedinglyclearthattherearenaturalautoantibodies presentoutsideofthesettingofautoimmunedisease.Infact,theyareubiq- uitousintheserumofallindividuals,regardlessofage,gender,orthepres- ence of disease (Nagele et al., 2013). Self-reactive immunoglobulins have alsobeenshowntobepresentinalltestedmammalsandinavarietyofbio- logical fluids, including blood, colostrum, saliva, and cerebrospinal fluid (CSF) (Avrameas, 1991; Avrameas & Ternynck, 1995; Bouvet & Dighiero,1998).Moreover,whiletheprofileofthesenaturalautoantibodies differsfromoneindividualtoanother,theyareremarkablystableovertime within a single individual (Lacroix-Desmazes, Mouthon, Kaveri, Kazatchkine, & Weksler, 1999; Mirilas, Fesel, Guilbert, Beratis, & Avrameas, 1999). The truth, it seems, is more strange and wonderful than our immunological forebears could have predicted. Itisnowimaginedthattherearevastnetworksofself-reactiveantibodies (autoantibodies) of multiple isotypes and affinities, working in concert to perform a variety of immunological and homeostatic tasks (Avrameas et al., 2007; Cohen, 2007). It is perhaps in these functions, which we are onlynowbeginningtocomprehend,thatautoantibodieswillhavethemost potency as biomarkers. 2. A CAUSAL ROLE FOR AUTOANTIBODIES REVEALED IN WELL-KNOWN AUTOIMMUNE DISEASES 2.1 Role of Autoantibodies and Protein Citrullination in Rheumatoid Arthritis Therelationshipbetweenautoantibodiesanddiseaseisprobablybestexem- plifiedbyrheumatoidarthritis(RA).RAisaprogressiveinflammatorydis- orderandcommoncauseofjointdeformityandpainintheagingpopulation (Turk,vanBeers-Tas,&vanSchaardenburg,2014).Inthelasttwodecades, RAhasbecomewidely regardedas anoutcome ofimmunedysfunction in whichone’sownproteinepitopesaretargetedbyautoantibodiesgenerated by the immune system. Several studies have identified some of the protein targets and causal pathways that lead to the generation of autoantigens. Rheumatoid factor (RF) and anticitrullinated peptide antibodies (ACPAs) are two types of autoantibodies commonly detected in RA patient’s sera.
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