ReviewPhaseSeparationandNeurodegenerativeDiseases:ADisturbanceintheForceAure´lieZbinden,1,2ManuelaPe´rez-Berlanga,1,2PierreDeRossi,1andMagdaliniPolymenidou1,*1DepartmentofQuantitativeBiomedicine,UniversityofZ€urich,Winterthurerstrasse190,8057Zurich,Switzerland2Theseauthorscontributedequally*Correspondence:magdalini.polymenidou@uzh.chhttps://doi.org/10.1016/j.devcel.2020.09.014SUMMARYProteinaggregationisthemainhallmarkofneurodegenerativediseases.Manyproteinsfoundinpathologicalinclusionsareknowntoundergoliquid-liquidphaseseparation,areversibleprocessofmolecularself-as-sembly.Emergingevidencesupportsthehypothesisthataberrantphaseseparationbehaviormayserveasatriggerofproteinaggregationinneurodegeneration,andeffortstounderstandandcontroltheunderlyingmechanismsareunderway.Here,wereviewsimilaritiesanddifferencesamongfourmainproteins,a-synu-clein,FUS,tau,andTDP-43,whicharefoundaggregatedindifferentdiseasesandwereindependentlyshowntophaseseparate.Wediscussfuturedirectionsinthefieldthatwillhelpshedlightonthemolecularmech-anismsofaggregationandneurodegeneration.THEFORCEAWAKENS:ANINTRODUCTIONINTOTHEFIELDOFLLPSInaneuronalsystemfar,faraway.Proteinaggregatesarevil-lainsoftheneurodegenerationEmpire,raidingbrainsandkillingneurons.Evadingthedreadedaggregation,thephasesepara-tionrebellionisareversibleprocessofmolecularself-assemblyfightingforfreemovementandexchangeofmolecules,allowingneuronstolivelongandprosper.However,membersofthephaseseparationrebellion,suchasa-synuclein,FUS,tau,andTDP-43arefoundinthesepathologicalaggregates.TurmoilhasengulfedthescientificrepublicwhenagrowingnumberofvoiceshypothesizedthatsomemembersoftherebellionmaysuccumbtoaberrantphaseseparationbehaviorandservethedarkaggregationprocessoftheEmpire.Thediscoveryofthebroadbiologicalroleofliquid-liquidphaseseparation(LLPS;Table1)asatrueForceconnectingmostas-pectsofcellularbiology,raisedmanyvoicesandcontroversiesinthescientific‘‘republic’’overthepastdecade.LLPSisthereversibleunmixingoftwomacromolecularsolution...
