Synaptic, Mitochondrial, and Lysosomal Dysfunction in Parkinson’s Disease 2019 Maria Nguyen.pdf

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Review
Synaptic,Mitochondrial,andLysosomal
DysfunctioninParkinson’sDisease
11111,
MariaNguyen,,DanielYsselstein,AlexSeverino,andDimitriKrainc*
ThediscoveryofgeneticformsofParkinson’sdisease(PD)hashighlightedtheHighlights
importanceoftheautophagy/lysosomalandmitochondrial/oxidativestressEmerginggeneticandmechanistic
studieslinksynaptic,mitochondrial,
,recentlyidentifiedPD-linked
andlysosomaldysfunctionasmajor
DNAJC6SYNJ1
genes,including(auxilin),(synaptojanin1),andthePDriskcontributorstothedegenerationof
midbraindopaminergicneurons.
geneSH3GL2(endophilinA1),havealsohighlighteddisruptionsinsynaptic
vesicleendocytosis(SVE)asasignificantcontributortodiseasepathogenesis.
Recently,endocyticgenes(DNAJC6,
LRRK2PRKNVPS35
Additionally,therolesofotherPDgenessuchas,,andinSYNJ1,andSH3GL2)havebeen
linkedtoParkinson’sdiseasepatho-

genesisoridentifiedasariskfactor
onthecontributionofdysfunctionalSVEtomidbraindopaminergicneurons’
forthedisease,implicatingarolefor
selectivevulnerabilityandhighlightpathwaysthatdemonstratetheinterplayofimpairedsynapticvesicleendocytosis
(SVE)inneurodegeneration.
synaptic,mitochondrial,andlysosomaldysfunctioninthepathogenesisofPD.
Amongthemodifiersofproteins
DopaminergicNeurodegenerationinPDinvolvedinSVEareLRRK2andparkin.
’’
Dopaminergicneuronsoftheventralmidbrainsubstantianigraparscompacta(SNc)playanLRRK2sandparkinsinvolvementin
thiscontextisthroughtheirphosphor-

ylationandubiquitinationactions,
tothedevelopmentofthecardinalmotorsymptomsofPD,suchastremor,rigidity,andslowedrespectively.
movements[1].TheidentificationofseveralgeneticformsofPDhasstronglyimplicated
mitochondrialandlysosomaldysfunctionaskeycellularprocessesthatcontributetoPDDysfunctioninSVEindopaminergic
neuronscanleadtoincreasedlevels
pathogenesis[1].However,therecentdiscoveryofseveralsynapticgeneslinkedtoPD
ofunpackaged,cytosolicDAthatis
pathogenesisorpredictedtoalterithashighlightedtheneedtofurtherinvestigatethe
subjecttooxidationandpathogenic
.

brieflydiscusstherelationshipbetweensynaptic,mitochondrial,andlysosomaldysfunctionin
dopaminergicneurodegenerationandthecompoundingeffectsoftheirinteractions.
ModesofSynapticVesicleRetrieval
SVEistheregenerationofsynapticvesiclesfromtheplasmamembranefollowingneurotrans-
mission[2].OneofthecommonmodesofSVEisclathrin-mediatedendocytosis,andgivenits
relevancetothediscussionsinthefollowingsections,weoutlinefirstthestepsinvolvedinthis

protein2(AP-2),AP180,andepsintothecytoplasmicsurfaceoftheplasmamembraneto
areaswherePtdsIns(4,5)P2lipidsareconcentrated[3].Theseadaptorproteinsregulatecargo

ubiquitin-interactionmotifsandisresponsibleforbindingubiquitinatedcargoduringendocy-
1
KenandRuthDaveeDepartmentof
tosis[2].Next,membranebenderssuchasFCHoandendophilinA1arerecruitedtotheplasma
Neurology,NorthwesternUniversity
membranewheretheybegintomoldanddirecttheinvaginationofthenascentlyformingvesicleFeinbergSchoolofMedicine,
Chicago,IL60611,USA
byinsertingintothelipidmembraneviaitsBARdomain[4](Figure1).FCHoalsocontainsan
additionalcargo-bindingsubunitsimilartoAP-2foranunknowncargo,implicatingitsroleinthe
earlystagesofSVE[2].AsthePtdsIns(4,5)P2lipid-enrichedvesicletakesonaroundand*Correspondence:
uniformshape,******@().
TrendsinNeurosciences,MonthYear,,:///
©.

(1)InvaginaƟon/(2)Fission(3)ClathrinuncoaƟng(4)Packaging(5)Vesicular
constricƟondopamine
Synapse
SynapƟccleŌ
DynaminEndophilinA1Synaptojanin1AuxilinHsc70ClathrinDopamine
’sDiseaseGenesPlayaRoleinSynapticVesicleEndocytosis(SVE).Theregenerationofsynapticvesicles
followingneurotransmissioninvolvestheconcertedeffortofvarioussynapticproteins,someofwhichhavebeenrecentlylinkedtoParkinson’sdiseaseoridentifiedas
riskfactorsforit(indicatedinredinthelegend,bottom).Clathrin-mediatedendocytosis,acommonmodeofSVE,involvesfivekeysteps,illustratedhereinthecontextof
dopamine-loadedvesicles.(1)Invagination/constriction:Followingtherecruitmentofadaptorandclathrin-coatproteinstotheplasmamembrane,endophilinA1
-coatedvesicle(CCV).(2)
Fission:,whosephosphatase
activitydephosphorylatessynapticvesiclemembranelipidstoreleaseadaptorproteins,allowingauxilintobindtotheCCV.(3)Clathrinuncoating:Auxilinisacofactorfor
hsc70,whichsimulatestheremovaloftheclathrincoatthroughitsATPaseactivity.(4)Packaging:Oncetheclathrincoatisfullyremoved,dopaminecanbepackaged
intothenascentvesicle.(5)Vesiculardopamine:Thedopamine-
thevesiclealsomitigateselevationofitscytosoliclevelsandpreventsdopaminefrombecomingoxidizedinthecytosol.
tothemembraneinterface[5–9].ThroughitsGTPaseactivity,dynaminstimulatesthefissionof
theclathrin-coatedvesicle(CCV)fromtheplasmamembrane[7].OncetheCCVisfree,
synaptojanin1usesitsphosphatasefunctiontodephosphorylatePtdsIns(4,5)P2toPtdsIns4P
andsubsequentlyPtdsIns[10,11].ThesedephosphorylationeventsreleaseAP-2,whichrelies
onPtdsIns(4,5)P2foritsvesiclebinding,andallowauxilintobindtheCCVthroughitsPTEN-like
andclathrin-bindingdomains[2,12].Auxilinisacofactorforhsc70anditsJdomainis
responsibleforrecruitmentoftheATPasetostimulateclathrin-coatremoval[2,12].Once
theCCVisuncoated,thenascentvesicleisthenpackagedwithneurotransmittersandquickly
transportedtovarioussynapticvesiclepoolsinanticipationofthenextneuronalstimulation.
Othermodesforsynapticvesicleretrievalhavebeenwelldescribed,includingkiss-and-runand
severalvariationsofbulkendocytosissuchasultrafastandactivity-dependentbulkendocyto-
sis[2,13,14].Thesemechanismsareinitiallyclathrinindependentandoccuronamuchfaster
,endophilinA1,
andsynaptojanin1[8,15].Inbulkendocytosis,followinghighneuronalstimulationalarge
membranousstructureinvaginatesfromtheplasmamembranecreatinganendosome
2TrendsinNeurosciences,MonthYear,,

intermediarywherecargosortingandsubsequentsynapticvesicleregenerationcanoccur[16].
Large-scaleinvaginationoftheplasmamembraneallowstheendosomalstructuretoretain
highPtdsIns(4,5)P2lipidlevels,whichcanleadtosubsequentclathrin-mediatedsynaptic
vesiclebuddingfromtheendosome[14].
TheregenerationofsynapticvesiclesthroughSVEisessentialtosustainneurotransmission

distinctproteinstermeddephosphins,whichareregulatedthroughphosphorylation–dephos-
phorylationevents[10].Classicallytheseproteinsincludedynamin,synaptojanin1,amphi-
physin1and2,andepsinamongothers[10].Althoughclathrin,AP-2,endophilinA1,andauxilin
havenowbeenshowntobephosphorylatedbyseveraldifferentkinases,whethercalcineurinis
themainregulatoryphosphatasefortheseproteinsremainsunknown[12,17,18].Underbasal
conditions,SVEproteinsareconstitutivelyphosphorylated,whichinhibitsthemfromassociat-
2+
ingwithotherproteinsintheendocyticpathway[10].Whentheneuronisstimulated,Caflow
2+
intothecellactivatesCa-dependentcalcineurinactivity,whichrapidlydephosphorylates
endocyticproteinstoenabletheirinteractionandrecruitmenttoendocyticsites[10,19,20].SVE
proteininactivationthroughrephosphorylationoccursonamuchslowertimescaleina

Minibrainkinase[21,22].However,thereremainsasignificantgapinourknowledgeofother
possibleproteinkinasesthatareresponsibleforthepropercontrolofSVE.
MutationsofSynapticGenesinParkinsonism
MultiplePD-linkedgenesinvolvedinSVEhaverecentlybeenidentified,suggestingthat

(auxilin)andSYNJ1(synaptojanin1),whichwereinitiallydescribedinatypical-Parkinsonism
patients[23–29].HomozygositymappingoftwopatientswithjuvenileParkinsonismrevealeda
deleterioussplice-sitemutation,-2A>G,inDNAJC6,thatledtoasignificantdecreasein
mRNAlevels[23].AseparatestudyfoundapatientwithaDNAJC6homozygoustruncating
mutation,Q734X,leadingto20%lossoftheCterminus,includingitsfunctionalJdomain
responsibleforbindinghsc70[24].Thusfar,thesemutationshavelinkedDNAJC6tojuvenile
,recentinvestigationsreportedadditionalDNAJC6
mutations,R927GandT741T,linkedtoearly-onsetPDcases[25].Thesemutationsresultedin
loweredauxilinexpressionandarepredictedtodecreaseitsoverallfunction[25].
Inaddition,R258QandR459PmutationsinSYNJ1wererecentlyreportedinseveralindependent
studiestobeassociatedwithjuvenileorearly-onsetPD[26–29].Thesemutationsarelocatedin
theSac1domainofsynaptojanin1andimpairitsphosphataseactivity[26–28].Interestingly,
synaptojanin1haploinsufficiencyledtodelayedSVEinmousemidbraindopaminergicbutnot
corticalneuronssuggestingthatlossofsynaptojanin1functioncould,inpart,contributeto
dopaminergicneuronvulnerabilityinPDpathogenesis[30].Last,SH3GL2(endophilinA1)was
identifiedinaPDrisklocusinalarge-scaleGWASmeta-analysis,linkingyetanothergeneinvolved
inSVEregulationtoPD[31].Collectively,thesesynapticendocyticgenesimplicatedefectiveSVE
asacontributortothedegenerationofmidbraindopaminergicneuronsinpatients.
AnimalknockoutmousemodelsofDNAJC6,SYNJ1,andSH3GL2haveallexhibitedendocytic
defectsatthesynapse,highlightingtheimportanceofproperSVEcontrolinmaintainingaxon
terminalintegrity[9,32,33].Itwaspreviouslyreportedthatthepresynapticcompartmentof
auxilinknockoutmicedisplayedcharacteristicsofdefectiveSVEincludingreducedsynaptic
vesicledensityandincreasedCCVsandmembranelessclathrincages[32].Interestingly,
follow-upstudiesfoundthatembryonicmouselethalityresultingfromgeneticablationofboth
TrendsinNeurosciences,MonthYear,,

GAK,anauxilinhomologandPDriskgene,andDNAJC6couldberescuedbyoverexpression
oftheGAKC-terminalfragmentcarryingboththeclathrin-bindingandJdomains[34–36].
AlthoughGAKandauxilinhaveredundantclathrin-uncoatingactionsinthecell,thesedata
-
more,lackofauxilininDrosophilaledtospecificage-relatedlocomotordeficitsandaccelerated
aSynuclein(aSyn)-mediateddopaminergicneuronlossinthismodel[37].Thisresultimplies

reports,thesynapsesofSYNJ1R258Qknock-inmicerevealeddrasticendocyticdefectsand
higherlevelsofendocyticintermediatessuchasCCVs[11].Additionally,dystrophicaxon
terminalswereobservedinthedorsalstriatumofthesemice,whichisaprimarysiteofSNc
dopaminergicneuronprojectionsinthebrain[11].Moreover,auxilinandparkin(PRKN)protein
levelswerereportedtobeelevatedinsynaptojanin1-mutantmice[11].Furthermore,endophilin
A1knockoutmousemodelsalsoreportedelevatedparkinlevelsaswellasaccumulatedCCVs,
highlightingapotentialfunctionalconnectionbetweentheseSVEproteinsandparkin[9,38].
TheRoleofaSyninSVE
aSyn,encodedbySNCA,isasolubleproteinlocatedinthepresynapticterminalthatisinvolved
intheregulationofsynapticactivity,plasticity,synapticvesiclepoolmaintenance,andtraffick-
ing[39,40].aSynfunctionhastraditionallybeenlinkedtosynapticvesicleexocytosis,although
whetherit