NeurodegenerativeTherapeuticsMarket

2016

Overview

• NeurodegenerativediseasesasdiverseasAlzheimer’s,Parkinson’s,andCreutzfeldt-Jakobdiseaseshareacommonpathogeneticmechanisminvolvingaggregationanddepositionofmisfolded proteins,whichleadstoprogressivecentralnervoussystemdisease• Althoughthetypeofaggregatedproteinandtheregionalandcellulardistributionofdepositionvaryfromdiseasetodisease,thesedisordersmayallbelinkedbysimilarpathwaysofproteinaggregationwithfibrilformationandamyloiddeposition• A widevarietyofneurodegenerativediseasescanbegroupedmechanisticallyasbrainamyloidoses,anoutlookthatyieldsnovelinsightsintopotentialtherapeuticapproachesthatmaybeapplicableacrossthebroadspectrumofneurodegenerativedisease

Commonneurodegenerativediseasecharacterizedbydepositionofaggregatedproteins

*SourcesfordataontheseslidesareintheNotessectionforeachslide

Summaryofimportantneurodegenerativediseaseproteins

Themisfolded conformationsofamyloid-β,tau,α-synuclein,huntingtin andsuperoxidedismutase1arecharacterizedbybundlesoftwisted,non-branching filamentsthatarecomposedofβ-sheetsthatinturnconsistofβ-strands

Modelforproteinmisfolding andfibrillization

Pathologyofneurodegnerative diseases

Prion-likediseaseproteintransmissioninneurodegenerativediseases.• Intemplate-directedmisfolding,thedepositedpathologicaldiseaseproteinsaretransformedfromtheirnormalconformation,viaintermediates,intofibrillar species

• Thesespecieshavethepropertiesofamyloid(forinstance,afibrillar ultrastructurethatconsistsofsheetsofβ-strands)andserveastemplatestodrivenormalphysiologicalversionsoftheproteintoadoptsimilarstructuralalterations

• Inaself-perpetuatingprocess,theprogressiveseededaggregationofconformationally changedproteinsresultsinintracellularaggregatesthatfragmentinto‘daughterseeds’.Finally,incell–celltransmission,pathologicalproteinsspreadtoanatomicallyinterconnectedneuronsandadjacentglialcellsvia anautocatalyticchain-reaction-likeprocess

Mitophagy inneurodegenerativedisease• Figure1|Overviewoftheautophagypathwayandthesitesofactionofdisease-associatedproteins.Thisdiagram• NatureReviews|Neuroscienceshowsasimplified versionofautophagy.Initiationofautophagy issignalledviatheactivityofthevacuolarprotein

• sorting34(VPS34) complex.Precursorvesiclesfusetoformpre-autophagosomal structuresthatgrowtoeventuallybecomedouble-membraned autophagosomes. Substratesfordegradationbyautophagyareengulfedbythesegrowingmembranesormaybesequestered intotheforming structurebyreceptorproteins.Thecompletedautophagosomes arethen traffickedtofusewithlysosomes.Theacidicenvironment inside thelysosomes ismaintainedbyATPases.ThislowpHisrequired forthecorrectfunctionofthelysosomal degradative enzymes(depictedasscissors)and,therefore, thebreakdownoftheautophagysubstrates.Perturbations throughout thepathway,frominitiationofautophagosome formation todegradation intheautolysosomes, havebeensuggestedtobeinvolvedinneurodegenerativediseases;somedisease-associatedproteinsfunctionatmultiplepoints intheprocess.Thekeypoints inthepathwayandtheselecteddisease-associatedproteinsthatarethought toactatthesepointsarehighlighted inboxes;therelevantdiseaseisindicatedinparentheses.AD,Alzheimerdisease;ALS,amyotrophic lateralsclerosis;ATG,autophagyprotein;ATP13A2,ATPasetype13A2;BPAN,β-propellerprotein-associatedneurodegeneration;CHMP2B,chargedmultivesicular bodyprotein2B;CMT2,Charcot–Marie–Toothdiseasetype2;HD,Huntington disease;HSP,hereditaryspasticparaplegia;HTT,huntingtin; LC3,microtubule-associatedprotein1lightchain3;LSD,lysosomal storagedisease;PD,Parkinsondisease;PICALM,phosphatidylinositol-bindingclathrin assemblyprotein;PS1,presenilin 1;SIGMAR1, sigmanon-opioid intracellularreceptor1;TFEB,transcription factorEB;WIPI4,WDrepeatdomainphosphoinositide-interacting protein4.

Initiationofmitophagy

Productionofbetaprotein

Amyloidcascadehypothesis

Casestudy:mutationslinkedtotemporaldementia

Pathologicaleffectsoftauaggregation

Conclusions

• Mostneurodegenerativediseasesarecharacterizedbypathologicallesionscomposedofaccumulationsofamyloid• Mutationsthatcausefamilialformsofthesediseasesarelinkedtoaccumulationoftheamyloid,andmousemodelsthatrecapitulatefeaturesofthesediseasescanbegeneratedbyengineeringamyloidaccumulationinthebrain• Indifferentdiseasestheamyloidiscomposedofdifferentproteinconstituents,butineachcasetherearelikelytobequitesimilarpathwaysofmisfolding,oligomerization,andfibrilformation• Eachstepinthesepathwaysmayprovidetargetsfortherapeuticdrugdevelopment