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InternationalJournalof
MolecularSciences
Review
CircularRNAs:EmblematicPlayersofNeurogenesisand
Neurodegeneration
MariannaD’Anca1,*,,2,ChiaraFenoglio1,3andDanielaGalimberti1,2
1FoundationIRCCSCa’Granda,OspedaleMaggiorePoliclinico,20122Milan,Italy;
francesca.******@(.);chiara.******@.******@(.);
daniela.******@.******@(.)
2DepartmentofBiomedical,SurgicalandDentalSciences,UniversityofMilan,20122Milan,Italy
3DepartmentofPathophysiologyandTransplantation,UniversityofMilan,20122Milan,Italy
*Correspondence:marianna.******@
Abstract:Inthefascinatinglandscapeofnon-codingRNAs(ncRNAs),circularRNAs(circRNAs)are
peepingoutasanewpromisingandappreciatedclassofmoleculeswithgreatpotentialasdiagnostic
-strandedRNAmolecules
,
similartoaberrantsplicingby-products,nowadays,
regulatetheexpressionoflinearmRNAtranscriptsatdifferentlevelsactingasmiRNAsponges,
,being
extremelyconservedacrossphylaandstable,cellandtissuespeciflc,mostlyabundantthanthelinear
RNAs,,circRNAs
areparticularlyexpressedinbrainandtheybuildupduringagingandage-
extraordinarypeculiaritiesmakecircRNAspotentiallysuitableaspromisingmolecularbiomarkers,
Citation:D’Anca,M.;Buccellato,.;circRNAs,emphasizingtheirroleinagingandpathogenesisofmajorneurodegenerativedisorders,
Fenoglio,C.;Galimberti,’sdisease,frontotemporaldementia,andParkinson’sdiseaseswithalooktowardtheir
RNAs:EmblematicPlayersofpotentialusefulnessinbiomarkersearching.
NeurogenesisandNeurodegeneration.
,23,:circularRNAs;Alzheimer’sdisease;frontotemporaldementia;Parkinson’sdisease;aging;
/neurogenesis;neurodegeneration
ijms23084134
AcademicEditor:MercèPallas
Lliberia
Received:24March2022
Accepted:6April2022CircularRNAs(CircRNAs)havelongremainedconcealeduntilanewgeneration
Published:,theyhavebeen
overlookedasartifactsofthesplicingprocess,butnowtheyundoubtedlyfallintoanew
Publisher’sNote:MDPIstaysneutralsubclassofnon-codingRNAs(ncRNAs)withsigniflcantperspectives[1].Tounderstand
withregardtojurisdictionalclaimsintheirimportance,sufflcetorememberthatonly2%ofRNAtranscriptsencodesforproteins
publishedmapsandinstitutionalaffll-versusmorethan60%oftranscribedRNAs[2].Thisimpliescrucialbiologicalfunctionsfor
iations.
,circRNAsareevolutionaryconservedacross
eukaryotictreeoflifeatsequenceandexpressionpatternlevels,especiallyinthebrain,
demonstratingtheirubiquitousfunctions[3,4].Additionally,circRNAsshowtissueand
Copyright:©
LicenseeMDPI,Basel,%ofthecerebralencodedgenomeproducescircRNAs[5].Furthermore,circRNAsare
ThisarticleisanopenaccessarticlegeneratedattheexpenseofregularmRNAtranscriptsunderlyingaregulatorymechanism
distributedunderthetermsandonmRNAamount,actingas“mRNAtraps”[6].Interestingly,aneuralspeciflcregulation
conditionsoftheCreativeCommonsofcircRNAproductionseemstobebecausemanycircRNAsareexclusivelyexpressed
Attribution(CCBY)license(https://inthebrainandinspeciflcbrainareasorinahigherpercentagewithrespecttoother
[4].CircRNAsareparticularlypresentinneurons,wheretheyarelocalizedin
/).thecytoplasm,
,23,:///ijms23084134:.
,23,41342of21
whytheyseemtobeconcentratedinthecerebellum,notoriouslydenseneuronalspines,
synapses,andneurons[5].Theyprobablycontributetoneuraldevelopmentasduring
neuronaldifferentiation,theirnumberincreases,varyingtheirexpressiontemporallyand
spatially[7].TheseflndingssuggestthatcircRNAsarecrucialforneuralfunctionand
,they
aredifferentlyexpressedduringsynaptogenesis,andinmanycases,withnocorrelation
withtheirlinearmRNAisoforms,highlightingsingularandspeciflcfunctionsofthe
circularizationevents[8].Inviewoftheabove,itisnowonderthatcircRNAsshouldplay
,ithasbeenreportedindifferent
organismsthatduringbrainaging,circRNAsdramaticallyincreasetheirexpressionlevels
comparedtothehostgenes[7,9–12].Thisisprobablyduetotheresistancetodegradation,
favoringtheirconcentrationinagedtissueasthebrain,densewithpostmitoticcells[13].
Additionally,malfunctioninanalternativesplicingprocessduringagingcouldfurther
implementthecircRNAbiogenesisinthenervoussystem[14].Sincenumerousworks
reportaprogressiveincrementofcircRNAsinthebrainduringaging,theirlinktoage-related
maladiessuchasAlzheimer’sdisease(AD),frontotemporaldementia(FTD),andParkinson’s
disease(PD)appearsnatural[15].Moreimportantly,circRNAsareabletocrosstheblood–
brainbarrier(BBB)andtheyareabundantinsmallextracellularvesicles[16,17].Thesetwo
features,combinedwiththeirextremestabilitytoexonucleaseaction,theirabundancein
agedneuraltissueaswellastheirselectivepresenceintypicalbraincells,makecircRNAsa
,thepresentreviewaimstoelucidaterecent
knowledgeofcircRNAsregardingtheirfundamentalroleinagingandneurodegeneration
withalooktowardtheirpotentialitiesasbiomarkersandtherapeutictargets.
:Biogenesis,ModeofAction,andFunctions
CircRNAsrepresentauniqueclassofnon-codingRNAswheretheends50and30are
covalentlyjoinedtoformaclosedcirclestructurewithalargevarietyinlengthandmecha-
nismsoforigin[18,19].Moreprecisely,circRNAscanbederivedfromexons(ecRNA)or
introns(ciRNAs),thepredominantclass,orbothexon-intron(ElciRNAs)transcribedfrom
pre-mRNAssequencesbyRNApolymeraseIIbyinvolvingspliceosomemachinery[20,21].
Realistically,circRNAproductionreliesonRNAbindingproteins(RBPs)andacombina-
tionofcis-elementsandtrans-factors[22].Actually,mostofthecircRNAsaregenerated
co-transcriptionallythankstotheescapeoflariatRNAsdebranchingorrecircularizationof
full-lengthintronswithunknownpostdebranchingeventsfortheintroniccircRNAs[21].
Instead,fortheexoniccircRNAs,back-splicingeventsfromconstitutiveexonscomeinto
play,compromisingthelinearmRNAs,inakindofcompetitivemechanismwhereitwould
seemthatcircRNAtranscriptsarepreferredwhenspliceosomeelementsorterminator
transcriptionfactorsarelimiting[6,22].Inthiscase,circRNAscouldregulatelinearmRNA
production,actingas“mRNAstraps”,sincemanycircRNAsaremoreabundantthan
correspondingmRNAlinearforms[6,23].Ontheotherhand,therehavebeenseveralre-
portedcaseswherethereisnocorrelationamongthelevelsofcircRNAsandthelinearhost
mRNA[4,6,10].OnecouldtheorizethecoexpressionofRBPsthatalternativelypromoteor
inhibitcircularizationaswellasthepresenceofpost-transcriptionaleventsthatstabilize
circRNAsorreducelinearhostmRNAhalf-life[6,23].Regardless,thecircularizationand
preferentiallyincytosolandtheirnuclearexportseemspartiallybasedontheirlength[24].
Likewise,intronicandsomeexoniccirRNAspreferentiallyconcentrateandfunctioninthe
nucleus[20].Additionally,circRNAscanbetranslocatedtootherdestinationsbyextracel-
lularvesicles[25].ThereisfewevidenceofthepresenceofcircRNAsinotherorganelles
suchasmitochondriathatrequirefurtheranddeeperinvestigations[26].:.
,23,41343of21
EvenifcircRNAs’ubiquitouspresencesuggestsconservativeandcriticalrolesin
organisms,,manypossiblemechanismsofcircR-
;
circRNAsserveas“miRNAssponges”.Inthisway,circRNAshindermiRNAactionon
targetsitesandexertaregulatoryroleongeneexpression[27].CDR1ascanbedeflned
asthecircRNA“miRNAsponge”parexcellencewithmorethan70conservedmiRNA-7
bindingsites;ithighlyinhibitsmiR-7activity[27].Furthermore,thiscircRNAisabundant
inthebrainanditsinteractionisreportedasbrainspeciflc[3].However,itcanbeseen
thatnotallcircRNAshadmiRNAbindingsites,andotherplausiblefunctionshavebeen
designated[28].Indeed,recentworkshavedemonstratedthatcircRNAsareabletointeract
notonlywithmiRNAs,butalsowithproteinsexertingmultipleeffectsonthem[29].Inter-
actionpatternsofcircRNAswithproteinsarenodoubtmoresophisticatedandintriguing
,nuclearcircRNAscanenhancethetranscriptionoftheir
hostgenes,bindingRNApolymeraseII(RNAPolII)[20].Whentheybindregulatory
RBPs,theycanactasproteinsponges,decoys,scaffolds,andrecruiters,modulatingand
influencingmanyfundamentalcellularprocessessuchascellcycle,apoptosis,senescence,
andcellsurvival,amongothers[21].CircRNAssuchasproteinspongesretainspeciflc
proteinsinthecytoplasm,,Circ-
Foxo3,sequesteringdifferentproteinsinthecytosolsuchasanti-stresstranscriptionfactors
asinhibitorofDNAbinding1(ID-1)andE2FTranscriptionFactor1(E2F1)orsenescence
proteinssuchasFocalAdhesionKinase(FAK),Hypoxia-InducibleFactor1-alpha(HIF-
1 )areabletoblocktheiranti-senescenceandanti-stressfunctions,enhancingcellular
senescence[30].Theycanvariatetheusualproteinfunction,decoyingasinglespeciflc
neuronsofAmyotrophicLateralSclerosis(ALS)diseasemodels,introniccircRNAscon-
centrateincytoplasmdecoyingTARDNA-Bindingprotein43(TDP-43)andavoiding
theaccumulationoftoxicTDP-43aggregates[31].CircRNAscanalsofavorinteractions
exampleiscircZNF827,whichnegativelyregulatesneuronaldifferentiationnucleating
hnRNPKandLtranscriptionfactorstorepressNGFR,consequently“tappingabrake”
onneurogenesis[32].CircRNAscanalsoactasproteinrecruiters,movingdeterminate
-eleven
translocationmethylcytosinedioxygenase1(TET1),ademethylase,totheFriendleukemia
integration1transcriptionfactor(FLI1)promoterregion,enhancingthetranscriptionofthe
hostgene[33].ThisadditionalfunctionmightallowcircRNAstranslocatingRBPstodistant
compartmentswithinneuronssuchassynapsesandsynaptosomewheretheyregulate
synapticfunction[4].CircRNAswerethoughtuntranslatablebutconsideringthatmostof
themoriginatedfromprotein-codingexonsandsomecontainedopenreadingframe(ORF)
andinternalribosomeentrysite(IRES),itisreasonabletobelievethattheycanencode
smallpeptides[34].Sofar,thisfeaturehasbeendemonstratedinvitroandinvivofora
subsetofcircRNAs,whileevidenceofendogenouscircRNAtranslationisabsent[35,36].
Finally,metabolismofcircRNAsissophisticallyregulatedbyRPBsmodulatingbiosynthesis
anddegradationaccordingtoaspeciflckindofcircRNAaswellastissueorcellfeatures
,
thismeansthatthesameRPBscanplayoppositerolesoncircRNAsbasedonwhichthe
,theexistenceofcircRNAscanberegulatedin
,circRNAproductioncompeteswithlinearforms
viaRNApolII,
morethanlessproliferatingones,sointheflrstoneswherethesplicingshouldbemore
efflcient,theportionoflineartranscriptscouldovercomethecircu