Fly Models of Human Diseases PDF
Preview Fly Models of Human Diseases
CURRENT TOPICS IN DEVELOPMENTAL BIOLOGY “Ameeting-groundforcriticalreviewanddiscussionofdevelopmentalprocesses” A.A.MosconaandAlbertoMonroy(Volume1,1966) SERIES EDITOR Paul M. Wassarman Department ofDevelopmental andRegenerative Biology IcahnSchool ofMedicine atMount Sinai New York, NY,USA CURRENT ADVISORY BOARD Blanche Capel Susan Mango Wolfgang Driever Philippe Soriano Denis Duboule Cliff Tabin Anne Ephrussi MagdalenaZernicka-Goetz FOUNDING EDITORS A.A. Moscona and Alberto Monroy FOUNDING ADVISORY BOARD Vincent G. Allfrey Dame Honor B.Fell Jean Brachet John C. Kendrew Seymour S. Cohen S.Spiegelman Bernard D.Davis Hewson W.Swift James D. Ebert E.N.Willmer Mac V. Edds, Jr. Etienne Wolff AcademicPressisanimprintofElsevier 50HampshireStreet,5thFloor,Cambridge,MA02139,UnitedStates 525BStreet,Suite1800,SanDiego,CA92101-4495,UnitedStates TheBoulevard,LangfordLane,Kidlington,OxfordOX51GB,UnitedKingdom 125LondonWall,London,EC2Y5AS,UnitedKingdom Firstedition2017 Copyright©2017ElsevierInc.Allrightsreserved. Nopartofthispublicationmaybereproducedortransmittedinanyformorbyanymeans, electronicormechanical,includingphotocopying,recording,oranyinformationstorageand retrievalsystem,withoutpermissioninwritingfromthepublisher.Detailsonhowtoseek permission,furtherinformationaboutthePublisher’spermissionspoliciesandour arrangementswithorganizationssuchastheCopyrightClearanceCenterandtheCopyright LicensingAgency,canbefoundatourwebsite:www.elsevier.com/permissions. Thisbookandtheindividualcontributionscontainedinitareprotectedundercopyrightby thePublisher(otherthanasmaybenotedherein). Notices Knowledgeandbestpracticeinthisfieldareconstantlychanging.Asnewresearchand experiencebroadenourunderstanding,changesinresearchmethods,professionalpractices, ormedicaltreatmentmaybecomenecessary. Practitionersandresearchersmustalwaysrelyontheirownexperienceandknowledgein evaluatingandusinganyinformation,methods,compounds,orexperimentsdescribed herein.Inusingsuchinformationormethodstheyshouldbemindfuloftheirownsafetyand thesafetyofothers,includingpartiesforwhomtheyhaveaprofessionalresponsibility. Tothefullestextentofthelaw,neitherthePublishernortheauthors,contributors,oreditors, assumeanyliabilityforanyinjuryand/ordamagetopersonsorpropertyasamatterof productsliability,negligenceorotherwise,orfromanyuseoroperationofanymethods, products,instructions,orideascontainedinthematerialherein. ISBN:978-0-12-802904-6 ISSN:0070-2153 ForinformationonallAcademicPresspublications visitourwebsiteathttps://www.elsevier.com/ Publisher:ZoeKruze AcquisitionEditor:ZoeKruze EditorialProjectManager:ShellieBryant ProductionProjectManager:VigneshTamil CoverDesigner:GregHarris TypesetbySPiGlobal,India CONTRIBUTORS H.J.Bellen BaylorCollegeofMedicine;JanandDanDuncanNeurologicalResearchInstitute,Texas Children’sHospital;PrograminDevelopmentalBiology;HowardHughesMedicalInstitute, Houston,TX,UnitedStates P.Bergman ClinicalMicrobiologyF68,KarolinskaInstitutet,KarolinskaUniversityHospital,Huddinge, Stockholm,Sweden C.Burke NeurologyResearch,Biogen,Cambridge,MA,UnitedStates R.L.Cagan IcahnSchoolofMedicineatMountSinai,NewYork,NY,UnitedStates L.Chakravarti PerelmanSchoolofMedicineattheUniversityofPennsylvania,Philadelphia,PA, UnitedStates R.T.Cox UniformedServicesUniversity,Bethesda,MD,UnitedStates J.M.I.Daenzer EmoryUniversitySchoolofMedicine,Atlanta,GA,UnitedStates Y.Engstro€m TheWenner-GrenInstitute,StockholmUniversity,Stockholm,Sweden J.L.Fridovich-Keil EmoryUniversitySchoolofMedicine,Atlanta,GA,UnitedStates D.C.I.Goberdhan UniversityofOxford,Oxford,UnitedKingdom P.Graham UniversityofMaryland,CollegePark,MD,UnitedStates F.Hamdy UniversityofOxford,JohnRadcliffeHospital,Oxford,UnitedKingdom V.L.Hewitt MedicalResearchCouncilMitochondrialBiologyUnit,Cambridge,UnitedKingdom S.X.Hou TheBasicResearchLaboratory,NationalCancerInstituteatFrederick,NationalInstitutesof Health,Frederick,MD,UnitedStates xi xii Contributors M.S.Kayser PerelmanSchoolofMedicineattheUniversityofPennsylvania,Philadelphia,PA, UnitedStates R.E.Kreipke UniversityofWashington;InstituteforStemCellandRegenerativeMedicine,Schoolof Medicine,Seattle,WA,UnitedStates M.Krench ThePicowerInstituteforLearningandMemory,MassachusettsInstituteofTechnology, Cambridge,MA,UnitedStates Y.V.Kwon UniversityofWashington,SchoolofMedicine,Seattle,WA,UnitedStates A.Leiblich UniversityofOxford;JohnRadcliffeHospital,Oxford,UnitedKingdom G.Lin BaylorCollegeofMedicine;JanandDanDuncanNeurologicalResearchInstitute,Texas Children’sHospital,Houston,TX,UnitedStates J.T.Littleton ThePicowerInstituteforLearningandMemory,MassachusettsInstituteofTechnology, Cambridge,MA,UnitedStates D.Mao JanandDanDuncanNeurologicalResearchInstitute,TexasChildren’sHospital;Programin DevelopmentalBiology,BaylorCollegeofMedicine,Houston,TX,UnitedStates E.H.Moscato PerelmanSchoolofMedicineattheUniversityofPennsylvania,Philadelphia,PA, UnitedStates V.Nadar NeurologyResearch,Biogen,Cambridge,MA,UnitedStates L.Pick UniversityofMaryland,CollegePark,MD,UnitedStates H.Ruohola-Baker UniversityofWashington;InstituteforStemCellandRegenerativeMedicine,Schoolof Medicine,Seattle,WA,UnitedStates S.Sanyal NeurologyResearch,Biogen,Cambridge,MA,UnitedStates A.Sen UniformedServicesUniversity,Bethesda,MD,UnitedStates S.SeyedoleslamiEsfahani TheWenner-GrenInstitute,StockholmUniversity,Stockholm,Sweden Contributors xiii H.R.Shcherbata MaxPlanckResearchGroupofGeneExpressionandSignaling,MaxPlanckInstitutefor BiophysicalChemistry,Go€ttingen,Germany S.R.Singh TheBasicResearchLaboratory,NationalCancerInstituteatFrederick,NationalInstitutesof Health,Frederick,MD,UnitedStates M.Sonoshita IcahnSchoolofMedicineatMountSinai,NewYork,NY,UnitedStates;KyotoUniversity GraduateSchoolofMedicine,Kyoto,Japan K.Trinh NeurologyResearch,Biogen,Cambridge,MA,UnitedStates A.J.Whitworth MedicalResearchCouncilMitochondrialBiologyUnit,Cambridge,UnitedKingdom C.Wilson UniversityofOxford,Oxford,UnitedKingdom PREFACE The fruit fly, Drosophila melanogaster, is arguably the most sophisticated model organism developed to date. With over a hundred years of genetics andthousandsofresearchersworldwide,toolstostudygeneexpressionand function—fromdetailedmolecularanalysisofsinglegenestogenome-wide analysesofregulatoryphenomena—areavailableatanunprecedentedscale. Results are shared freely among Drosophila researchers through informa- tional databases and repositories such as FlyBase, collections such as the Bloomington Stock Center that distributes fly lines at a minimal cost, and thehistoriccollegialnatureofinteractionamongflyresearchers.Inaddition tobothpastandongoingcontributionstobasicresearchinalmosteveryarea of science, Drosophila has now been established as a model to study human disease.Withorthologsofmorethan60%ofhumandisease-causinggenes, often present in single copy in flies but duplicated in vertebrates, and the wealth of tools available to assess gene function, genetic interactions, and environmentalinfluences,Drosophilaisanidealsystemforelucidatingmech- anisms underlying pathologies. This special volume provides examples of someofthebest-developedflymodelsforavarietyofhumandiseases.Many of these affect the nervous system, but the types of diseases that have been effectivelymodeledspanabroadrange,frommetabolicdisorderstocancer to bacterial infections. In each chapter, the basic pathologies in human patients and the parallels to Drosophila biology are discussed. The strengths of Drosophila as a model are presented, as well as weaknesses of its use as a model system, important to keep in mind for accurate translation to the human condition. Mitochondrialdiseasesareauniqueandcomplexsetofdiseasesthatare maternallyinheritedanddifficulttodiagnoseandtreat.SenandCoxreview theuseofDrosophilatostudymitochondrialdiseaseandmitochondrialinheritance. They review existing fly models for several mitochondrial diseases and methodology available in the fly to generate targeted mutations in mitochondrial DNA. Finally, they discuss recent findings on the role of mitochondrial purification during oogenesis and experiments in Drosophila that are unraveling how this is achieved. Whileinsectsdonothaveadaptiveimmunesystems,theysharewithver- tebrates an innate immune system. In fact, much of our understanding of innateimmunitycomesfromDrosophilaresearch.AsreviewedbyBergman, xv xvi Preface Esfahani, and Engstro€m, flies and humans also share microbial flora that influencehealth.Studiesofhost–microbeinteractions,whichincludeshared intracellularsignalingpathwaysandeffectormechanisms,arerevealingbasic mechanisms utilized by animals to both protect against microbial invasion and to promote the growth of a healthy microbiome. Ruohola-Baker and coworkers present a discussion of contributions made using Drosophila to study pathophysiological mechanisms underlying muscledegenerativedisorders,includingDuchennemusculardystrophyandspi- nal muscular atrophy, as well as muscle wasting seen in cancer and other human disease. They point to genetic interaction screens in flies that have identified pathways which could be targeted for therapeutic intervention in these and other muscular diseases. A number of chapters focus on the use of Drosophila to study neuronal disease.Lin,Mao,andBellenfocusononedevastatingdisease,amyotrophic lateral sclerosis (ALS). A number of genes have been implicated in familial ALS and, given their conservation, Drosophila provides a model to study their mechanisms of action. The authors propose that defects in RNA andproteinhomeostasisbuilduponeachothertocauseaccumulatingpro- teinaggregationthatispathologicalinALS.Resultstodateimplicateabnor- malities in pre-mRNA splicing, protein folding, ER stress, proteasomal degradation,andproteinmislocalizationasunderlyingbasesfordisease.This review highlights the use of Drosophila as an assay system to uncover the functionofgenesassociatedwithdiseaseinhumanstudies,andthepotential the fly system has to reveal mechanism of action of mutations found in human patients. Hewitt and Whitworth similarly focus on a single neurodegenerative disease, Parkinson’s disease (PD). Interactions between and mechanism of actionofseveralgenesassociatedwithandcausalforPDhavebeenstudied in Drosophila. Among others, the authors discuss the role of parkin in regu- lating mitochondrial dynamics, a mechanism first elucidated in studies in Drosophila.KrenchandLittletondiscussusingfliestostudythemechanisms underlying neurodegenerative disorders associated with expanded poly- glutamine tracts, such as Huntington’s diseases. They highlight progress made using Drosophila models to explain the underlying basis of disease andsuggestapproachestousingthesemodelstoidentifyandassesstherapies, including genetic suppressor screens that have the power to both dissect genetic interactions and identify potential drug targets. Sanyalandcoworkerstakeaslightlydifferentapproachtodiscussingneu- rodegenerative diseases, such as PD, by reviewing the importance of Preface xvii interactions between genes, age, and environment in disease onset and progression. They look toward future “intersectional experiments” that combine genetic approaches in the fly model with systems biology and “omics” to reveal complex interactions that lead to full-blown disease. Whilehighlightingmanystrengthsofferedbyflygenetics,theyalsoremind thereaderabouttheneedfordeeperunderstandingofthemolecularbasisof cellular defects before extrapolation to the human condition based upon grossly similar phenotypes. One of the more unexpected areas of fly research that proved to effec- tivelymodelhumanconditionsissleepresearch.Thisareaexplodedinrecent yearswiththeidentificationofgenesimpactingcircadianrhythmsandsleep activity in flies. Kayser and coworkers review studies of specific regions of the brain, neuronal circuitry, and signaling pathways that are highly con- served between flies and humans that play roles in sleep–wake cycles, responsetodeprivation,caffeine,andotherstimulants,impactingsleeppat- ternsaswellaslearningandmemory.Theypointtoearlystudiesinthisfield that identified the period (per) mutation in flies—a gene later implicated in human sleep disorders, and describe additional fly mutants that effectively model human neurodevelopmental, psychiatric, and sleep disorders. Drosophila has served as an excellent model for studies of cancer, as flies harbor similar oncogenes and tumor suppressor genes to humans, and mutationsresultinovergrowthandmetastasis,similartothatseeninhuman disease.SonoshitaandCaganreviewtheidentificationofgenesresponsible for overgrowth in Drosophila, which contributed to the finding that loss of cell polarity is a key feature of malignancy. They give examples of genes identifiedinDrosophilathroughgeneticmodifierscreensthatcanbeplaced inorderedpathwaysusingflygenetics,providinginsightintomechanismsof action.Theynextreviewmodelsofdifferenttypesofcancerthathavebeen developedinfliesandhighlightinteractionsbetweendietandgenotypethat are likely to prove important for cancer treatment. Finally, these authors emphasize the potential of Drosophila for drug screening in whole animals, citing,amongothers,thecontributionofaDrosophilamodeltotheapproval ofvandetanibasatargetedtherapyforhumanpatients,andprojectsunder- way to use fly models expressing specific oncogenes to test new, rationally designed chemistries. The role of stem cells in cancer is a major focus of recent research. Drosophila is a particularly good model here, not only because of the pow- erful genetics and numerous classes of identified stem cell lineages, but becausetherearenoregulatoryissuesconstrainingresearch.HouandSingh xviii Preface review a number of recent findings on the role of stem cells in tumor for- mationandprogressionindifferentstemcellpopulationsinDrosophila.They discusstherolesofsignalingmoleculesandpathways,providingexamplesof howDrosophilaresearchhascontributedtoourunderstandingofhowstem cell tumors initiate and propagate. They discuss molecular differences between normal and tumorigenic stem cells, and resistance of stem cells to standard therapies. Wilson and coworkers focus on a specific cancer type—prostate cancer—and ways in which the Drosophila accessory gland has been used to model this disease. They highlight the rather unexpected parallelsbetweenDrosophilaandhumanorgansystemshereandhighlycon- servedcellularmechanismsthatcontrolexosomeformationandsecretion,a classofsecretedvesiclesthathavebeenimplicatedintumormicroenviron- ments as well as metastasis. Lastly, Drosophila have also been used effectively to model metabolic dis- orders.DaenzerandFridovich-Keildiscussdiseasesofgalactosemetabolism, primarilyresultingfromabnormalitiesinLeloirpathwayenzymeswhichare shared between flies and mammals. Functional similarities have also been demonstrated: for example, similar to classic galactosemias in human, flies carrying mutations in the orthologous gene fail to thrive in the presence of galactose and this failure was rescued with a human transgene, demon- stratingfunctionalconservation.Thesestudiesandothers,includingidenti- fication of motor defects and impacts on life span that parallel phenomena seen in patients, make flies and excellent model to study genetic, environ- mental,andpharmaceuticalinterventionsforthisimportantclassofdisease. GrahamandPickdiscussDrosophilamodelsofdiabetesandrelateddisorders. They describe fly models that have been generated for both Type 1 and Type 2 diabetes, and approaches to study metabolic disorders that are influenced by diet and other environmental factors. While this volume was being assembled, a similar collection of articles was published (Perrimon, Bonini, & Dhillon, 2016). In that special issue of DMM, Bellen and coworkers provide a “Poster” illustrating three ways in which Drosophila research contributes to the study of human disease: reversegenetics,forwardgeneticsandadiagnosticstrategy,orpipelinethat utilizestheUAS/GAL4systemtoassesstherolesofcandidategenes(Ugur, Chen,&Bellen,2016).MostofthechaptersinthisvolumeofCTDBillus- tratetheuseoftheseapproachestotackletheunderlyingbasesofarangeof human disease. I refer the reader to both sets of collections to learn more aboutgeneralapproachestodiseasemodelingandtoprogressmadeonspe- cific disease types. Overall, enormous headway has been made in recent Preface xix years modeling human diseases in flies. This work paves the way for the development and refinement of additional models and future progress in translating these findings to effective drug development and disease intervention. LESLIE PICK REFERENCES Perrimon,N.,Bonini,N.M.,&Dhillon,P.(2016).Fruitfliesonthefrontline:Thetrans- lationalimpactofDrosophila.DiseaseModels&Mechanisms,9(3),229–231. Ugur,B.,Chen,K.,&Bellen,H.J.(2016).Drosophilatoolsandassaysforthestudyofhuman diseases.DiseaseModels&Mechanisms,9(3),235–244.
The list of books you might like
