Cysteine
oxidation
and
redox
signaling
in
dopaminergic
neurons
physiology
and
in
Parkinson’s
disease
Chiara
Milanese
1,
Ce´sar
Paya´n-Go´mez
1,2and
Pier
G
Mastroberardino
1,3Parkinson’sdisease(PD)isaneurologicaldisorderaffecting
dopaminergicneuronsinthenigrostriatalpathwaysofthe
brain.PDisamultifactorialdiseaseanditscausesshouldbe
soughtindetrimentalinteractionsbetweengenesand
environment.Sinceearlymechanisticstudies,excessive
oxidation–oroxidativestress–emergedasarecurringand
fundamentalpathogenicmechanism,andconsequently
receivedsignificantattention.Morerecentevidenceobtained
atsingle-cellresolution,however,indicatesthatdopaminergic
neuronsinthesubstantianigradisplayincreasedoxidation
levelsalsoinnormal,physiologicalconditions;differentlythan
pathologicaloxidation,theimportanceofthisphenomenonis
underappreciated.Thenigrostriataldopaminergicsystemis
involvedinbehavioralstrategiesthathavebeenunderstrong
evolutionarypressure.Itisthereforeimprobablethat
physiologicaloxidationindopamineneuronsisaccidental.
Here,wereviewrecentliteraturetoarguethatmoderate
oxidationimprovesredoxsignaling–whichindopamine
neuronsisintertwinedwithelectrophysiologicalactivityandis
importanttoregulatedopaminerelease–andalsohasa
protectiverole.Wealsoreasonthatphysiologicaloxidation
providesanexampleofantagonisticpleiotropytherefore
offeringanadvantageduringreproductivestagesoflifewhile
becomingdetrimentalduringaging.Collectively,webelieve
thattheseobservationsprovideanewperspectiveinthe
biologyofdopaminergicneuronsandinPD.
Addresses
1DepartmentofMolecularGenetics,ErasmusMC,Rotterdam,The Netherlands
2
FacultaddeCienciasNaturalesyMatema´ticas,Universidaddel Rosario,Carrera24,63C-69Bogota´,Colombia
3DepartmentofLife,HealthandEnvironmentalSciences,Universityof L’Aquila,L’Aquila,Italy
Correspondingauthor:
Mastroberardino,PierG(p.g.mastroberardino@erasmusmc.nl)
CurrentOpinioninPhysiology2019,9:73–78
ThisreviewcomesfromathemedissueonRedoxregulation
EditedbySrutiShivaandMiriamCortese-Krott
ForacompleteoverviewseetheIssueandtheEditorial
Availableonline8thMay2019
https://doi.org/10.1016/j.cophys.2019.04.025
2468-8673/ã2019TheAuthors.PublishedbyElsevierLtd.Thisisan openaccessarticleundertheCCBYlicense(http://creativecommons. org/licenses/by/4.0/).
Parkinson’s disease (PD)isaneurodegenerative disorder primarilyaffectingdopaminergicneuronsinthenigrostriatal
pathwaysofthebrain.Dopaminergiclossdisplays anatomi-calspecificityandismorepronouncedthelateralventraltier of the substantia nigra pars compacta (SNpc); dopamine neuronsintheventraltegmentalarea(VTA)arerelatively spared[1].PDetiopathogenesisiscomplexandstemsfrom detrimentalsynergiesbetweengeneticandenvironmental factors,ultimatelyperturbingcrucialprocessesinthecell. PDislargelysporadicandmonogenicformsrepresentonly 5%oftotalcases[2].StudiesonmonogenicPD,however, havebeeninstrumentaltounravelpathogenicmechanisms. At present, PD has been associated with 19 loci, which in turn have been unambiguously assigned to 11 genes (PD genetics hasbeenreviewedinseveralexcellentarticles,e.g.Ref.[3]). The latter are involved in different biological processes, from protein quality control to endocytic trafficking, to redox homeostasis, therefore reinforcingthe complexity of PD etiopathogenesis.
Oxidation
and
PD
Despite the recognized intricacy of PD pathobiology, however, oxidative stress received continued attention since theseminalwork ofLangstonet al.[4]describing parkinsonisminyoungsubjectsintoxicatedwithMPTP. Follow-up studies,infact,demonstratedadirect inhibi-tory effectof MPTP onmitochondrial respiratory com-plex Iwith consequentincreaseinreactive oxygen spe-cies(ROS)production[5].Afteritsdetectioninpatients’ specimens,oxidativestressrapidlybecameregardedasa highlyplausiblePDmechanism[6,7].Importantly, altera-tionsinredoxhomeostasishavebeendetectedinanimal modelsharboringmutationsinPD-associatedgenes[8]. Additionally,PDmodelinglargelyreliesoninductionof oxidativestressandvirtuallyalltheacceptedtoxicological modelsarebasedonchemicalsthatultimatelyfunctionas pro-oxidants [9]. Oxidative stress, therefore, remains a recurrentfactorofbothgeneticandidiopathicPD,anda point of convergence in the pathogenic cascade. More recently,theconceptofoxidativestressinPDevolvedin lightofthecrucialroleof oxidationinnormalbiological function,wherephysiological alterationsofthe intracel-lularoxido-reductive(redox)statemodifysensitive resi-dues in proteins to modulate their activity [10]. The processlargelyoperatesviareversibleoxidationofthiols in cysteine residues and is referred to as thiol redox signaling.
The topic of oxidative stress and redox signaling in neurodegenerationandinPDhasbeencomprehensively reviewedinseveralandevenveryrecentarticles,anditis not ourintention to revisit theinformation provided in
these excellent publications [11–13]. We would rather liketoemphasizefewunderappreciatedaspects concern-ing the redox metabolism of dopaminergic neurons in normal conditions and the potential physiological consequences.
Oxidation
and
dopaminergic
neurons
Dopaminergicneuronshavedistinctiveredoxproperties. Here,afirstsupportive evidencecomes fromstudiesin toxicological models of PD, which clearly show that selective dopaminergic degeneration can be elicited notonlybymoleculesspecificallytargetingdopaminergic neurons (e.g.MPTP), but alsobychemicalsacting sys-temically, for example rotenone and paraquat [14,15]. Another important evidence comes from studies that measure the intracellular redox state of dopaminergic neurons.Guzmanetal.[16]usedaredox-sensitivegreen fluorescentprotein(roGFP) [17]to demonstratethat in brainslices, innormal conditions(i.e.in theabsenceof pathology), dopamine neurons in the SNpc are more oxidized than those in the VTA. roGFP equilibrates – very slowly [18] – with the GSH/GSSG redox couple. Here, it should be emphasized that redox homeostasis relies also on additional couples, for instance thiols in thioredoxins [19,20], and that these systems are not at equilibrium, that is oxidation in one couple does not necessarilyimpliesoxidation intheother[21]. Informa-tioninferredwithroGFPisthereforenecessarilylimited to aspecific aspectof theintracellular redoxstate.Ina parallel approach, we took advantage of thiol-specific probesconjugatedto fluorescentdyesto achieve differ-entiallabelingofoxidizedandreducedcysteinestoinfer the global thiol/disulfide redox state in dopaminergic neurons at single cell level [22,23]. Our experiments confirmed higheroxidation in dopaminergicneurons of theSNpcwhencomparedtothoseoftheVTAortoother neurochemicalsubtypes ofneurons in thecortex[23]. While the method we developed and used in these measures cannot discriminate between specific redox couples, it provides an overview of the general redoxstate of the cell. Incombination with the results ofGuzmanetal.,ourstudyprovidesconvergingevidence that the thiol/disulfide redox state is oxidized in dopa-minergicneurons,innormalconditions,withoutongoing pathology.
Which
are
the
causes
underlying
increased
oxidation?
Increasedoxidationinthethiol/disulfideredoxcouplein dopaminergicneuronsisconsistentwithotherelements. Some evidence indicates that expression of ROS scav-enging enzymes catalase, Cu/Zn SOD dismutase, and glutathione peroxidase is lower in the SNpc than in theVTA[24,25].To refinethose observations,we took advantage of publicly available datasetsfrom transcrip-tomic studies performed at single-cell level [26] to explore the expression levels of key genes in redox
metabolism in embryos and seven days old mice. We found that expression of redox genes significantly decreasesafterbirth;however,wecouldnotdetectmajor visibledifferencesbetweendopaminergicneuronsinthe SNpcandthoseintheVTA(Figure1).Thesedatadonot excludedifferences,whichcouldbedetectableatprotein level,but certainly suggestthat there are noostensible transcriptional differences in SNpc dopaminergic neurons.
TheSNpcalsocontainshighironlevels[27],whichcan induceoxidation,especiallyincombinationwithH2O2
viaFentonchemistry[6].BecauseH2O2isabundantly
produced by the enzyme monoamine oxidase during dopamine degradation, dopaminergic neurons in the SNpc appear to be particular inclined to oxidation. Finally, high production ofROS has been also attrib-uted to the distinctive electrophysiological properties ofSNpcdopaminergicneurons. Somestudiesindicate thatpacemakingactivity(describedbelowinthetext) dependsoncalciuminflux through voltage-dependent Cav1.3channels,andthatcalciumisbufferedby mito-chondria,whichinturnproducesuperoxideduringthe process [18,28]. For sake of completeness, it should alsomentionedthatotherexperimentsattributealess prominent roletocalcium indopamineneurons pace-makingactivity especiallyinaging,whichremainsPD majorrisk factor [29,30]. Nonetheless, data generated independently,usingdifferentapproaches,are consis-tentwiththeobservationthatthethiol/disulfideredox stateinSNpcdopamineneuronsismoreoxidizedthan inother neuronalsubtypes innormal conditions.
Oxidation
and
evolution
UnlikeoxidativestressinPD,theconceptthatSNpc dopamineneuronsdisplayincreasedoxidation alsoin normal conditions has not received commensurate attention. Yet, this is an important issue because it ishighlyconceivablethatabasaloxidizedredoxstate underlies the particular vulnerability of SNpc dopa-mineneuronsto pro-oxidants,therefore predisposing to PD pathogenesis. Here, it should also be empha-sized that available evidence indicates that SNpc dopamine neurons do not put in place mechanisms tomitigateoxidationinnormalconditions,asinferred fromlevelpreviousliteratureandfromtranscriptomic analysisatsingle-cell level [26]ofmajor redox genes
(Figure 1). It is very unlikely that this distinctive
biochemical characteristic is accidental. The dopa-mine system is in fact essential to adapt behavioral strategiestoenvironmentalstimuli:givenan external input,it has a role in selecting the most appropriate motor program and in learning new advantageous schemes. Simplyput, thedopamine systemis crucial to learn how to discriminate between positive and negative stimuli, and what actions should be put in placetotake advantageof beneficialsituations while
avoidingdangerousones[31,32].Itistherefore obvi-ous that thedopamine systemhasbeenunder strong evolutionary pressure. Thequestion is therefore why dopamineneuronsevolvedwithaphysiologically oxi-dized intracellular environment despite this feature posesrisksforneurodegenerativediseases.Obviously, it is highly plausible that this question has multiple answers. One possibility, however, is that increased oxidation is functional for intense redox signaling, which is required in dopamine neurons in the SNpc to fulfiltheirphysiological properties.
Physiology
of
DA
neurons
and
redox
signaling
Activity ofdopaminergicneurons andsubsequent regu-lation of dopamine release is a complex topic that has been reviewed in several excellent articles [31,32,33]. Forthepurposesofthisreview,itissufficienttoprovidea succinct overview of the process. Dopamine neurons display two dominant activity patterns (i.e. firing pat-terns),thetonicand thephasicmodes.Thetonicmode is characterized by spontaneous, regular activity that is associated with a steady level of dopamine, which is necessary to maintain normal function in the related
Figure?1 Column Z-Score E15.MB.2 E15.MB.1 P7.MB.4 P7.MB.1 P7.MB.2 P7.FB.2 P7.FB.1 P7.OB.3 P7.OB.1 P7.OB.2 Prdx5 Prdx1 Prdx6 Prdx4 Prdx3 Prdx2 Nxn Gclc Txnrd2 Glrx Txnrd1 Glrx2 Glrx5 Txn1 Glrx3 Txn2 P7.MB.3 E15.FB.1 E15.FB.2 -2 0 2 Color Key
Current Opinion in Physiology
Two-wayclusteranalysisofsinglecellnextgenerationRNAsequencingdata(GSE108020)[26]fromembryonic(E15)andpost-natal(p7)mice illustratingexpressionlevelsofmajorgenesinvolvedinredoxmetabolism.Whileexpressionofredoxgenesisclearlyhigherinembryonicneurons, inpost-natalspecimensnoobviousdifferencescanbeappreciatedbetweendifferentareas,includingbetweentheSN(MB.4)andtheVTA(MB.1). AbbreviationsforE15:FB.1:forebrainneuroblast;FB.2:post-mitoticforebraintyrosinehydroxylase-positive(Th+)neurons;MB.1:midbrain neuroblast;MB.2:post-mitoticmidbrainDAneuron.AbbreviationsforP7:FB.1:arcuatenucleusneuroendocrineTh+neurons;FB.2mixtureof arcuatenucleusTh+subtypes;MB.1:ventraltegmentalarea;MB.2:postnatalneuroblast;MB.3:periaqueductalgrayarea;MB.4:substantianigra; OB.1:leastmatureTh+neurons;OB.2:progressivelymaturingTh+neurons;OB.3:mostmatureTh+neurons.Genesabbreviations:Prdx1-6: peroxiredoxin1–6;Nxn:nucleoredoxin;Gclc:g-glutamylcysteinesynthetase,glutamatecysteineligase;Txnrd1-2:thioredoxinreductase1–2; Glrx1-5:glutaredoxin1–5;Txn1-2:thioredoxin1-2.
circuits[34,35].Incontrast,thephasicmodeis character-izedbysharp activitychanges,thatisbursts,thatcause largechangesindopaminelevelsandmaybeinitiatedby different types of reward related stimuli [34–36]. The phasicmodeisthereforehighlyrelevantfromthe stand-point of the behavioral response. Among the various factorscontributing to bursting control, at least by two typesofionicchannelshavearelevantroleintheprocess: the ATP-sensitive potassium (K-ATP) channels and NMDAreceptors,whichcanalsoactinconcertto poten-tiatetonicfiring[37,38].
K-ATPchannelsare octamericcomplexes composed of fourpotassiuminwardlyrectifyingchannels(Kir6.X, typ-icallyKir6.2inneurons[39])formingthepore,andfour sulfonylureareceptorunits(SUR1orSUR2)that consti-tutetheregulatoryunits [40].Openingof K-ATP chan-nelscanbeelicitedbymultiplefactorsassociatedwiththe metabolicstatusof thecell(reviewed in Ref.[41]) and causesmembrane hyperpolarization, which in turn cul-minates in reduced electricalactivity. This mechanism canserve as aneuroprotective strategyin conditions of metabolic distress such as hyperactivity during seizure [42,43]orexcitotoxicity[44].InSNcdopaminergic neu-rons, redox activation – for instance following H2O2
mediatedopeningofK-ATP–emergedasanimportant mechanismtoregulatedopaminerelease[45,46].The mechanism operates viamodification of redoxsensitive cysteine residues [47], is mediated by the regulatory subunit SUR1 [45], and one study identified at least two-specificresiduesintheregulatorysubunitSUR1via site-directed mutagenesis [48]. Because expression of SUR1 has been associated with metabolic sensitivity and predisposition to dopaminergic degeneration, and in light of the distinctive redox properties of SNpc dopamine neurons, these findings are highly relevant forbothdopamineneuronsphysiologyandPD[49,50]. Also,NMDAreceptors,whichmediatecalciuminfluxin the cell, can contribute to SNpc dopamine neurons’ burstsinphasicmode.NMDAreceptoractivationalone, however,isnotsufficienttoswitchneuronstothephasic mode and require other hyperpolarizing currents, for instance upon extrusion of sodium ions [51], or by K-ATP channel activation, which potentiate phasic burst firing[38].Also NMDA receptorsare redoxregulated and oxidation of sensitive cysteine residues inactivates thechannel[52,53].Thus,whilebothNMDAreceptors andK-ATPchannelssensethesurroundingredoxstate, oxidationelicitsoppositeconsequences.The physiologi-calconsequencesofthedifferentredoxbehaviorofthese channels will have to be addressed in future studies; however,thecombinationof redoxmediatedclosure of NMDAreceptorand K-ATPchannelopening may pre-ventexcitotoxicitywhilecontrastingoverexcitability,and mayreflectaconcertedstrategytoprotectagainst oxida-tivestress.
Thiol/disulfide
redox
state
and
H
2O
2signaling
Collectively, the discussed findings highlight the rele-vance of H2O2 signaling for the physiology of SNpc
dopaminergic neurons and its importance in governing behavioral aspects that have been highly exposed to evolutionary pressure (also discussed in Ref. [28]). Thequestioniswhetherincreasedintracellularoxidation inthethiol/disulfidenetworkcouldbebeneficialforthis process.
ThemechanicsgoverningH2O2redoxsignalingare
com-plexandsomeoftheiraspectsofareonlyrudimentarily understood (reviewed in Ref. [54]). It is for instance unclear how specificity is ensured in H2O2 signaling
and in particular which chemical, biological, and struc-tural criteria drive targeted modification of a certain cysteine residue. Another major issue stems from the very modest reactivity of protein thiols toward H2O2
(k101–102M 1s 1) [55]. How cancysteine modifica-tion occur in a time frame compatible with neuronal physiologicalneeds?Itcouldbearguedthatthereaction efficiency would be highly improved in proximity of H2O2sources,wherelocalconcentrationsareparticularly
high.Atleast in thecaseof K-ATPchannels,however, some evidence indicates that H2O2signalingoriginates
frommitochondriaratherthanplasmamembraneproteins such as NADPH oxidase [46], and proximitybetween H2O2 and its target is therefore questionable. Further
complication arises from the far higher rate constants (k105–108M 1s 1) of H2O2 scavenging enzymes –
forinstance peroxiredoxins(Prxs)– whichare generally abundantlyexpressed.Veryrecentevidencesuggeststhat PrxsmightmediateH2O2signalingtoovercomelowrates
of reactionand lackof specificity[56];nonetheless, it cannotbeexcludedapriorithatPrxsmayquench,oreven neutralize,H2O2functionas secondmessenger.
We hypothesize that constitutively higher oxidation in the thiol/disulfide couple could favor H2O2 at least in
threeways.(1)Oxidationinasubpopulationof intracel-lular thiolswould increasetherelative concentration of H2O2,thereforefavoringitsactionasasecondmessenger.
Thishypothesis impliesthatfactorssuch as theinvivo redox potential of protein thiols will determine which residues will be oxidized in basal conditions, and also impliesthatproteinssuchasK-ATPchannelswillremain in a reduced state. Redox proteomic studies will be necessarytoaddressthispossibility.Additionally, experi-mentsinwhichmeasuresofredoxsignalingeffectiveness will be paralleled by rigorous measures of intracellular redoxstateasinglecelllevelwillbenecessaryto conclu-sively assess the effect of dopaminergic neurons basal oxidation on H2O2 as second messenger. (2) Increased
cysteineoxidationcouldalsoblocktheactivesiteofPrxs, whichare particularlysensitive to H2O2mediated thiol
oxidation,asalsoindicated byredoxproteomicsstudies [57,58]. (3) Multiple lines of evidence indicate that
bioavailability of ROS is higher in SNpc dopaminergic neuronsbecauseofhigherproductionand/orlower scav-enging.Inthischemicalcontext,anincreaseinreversible cysteine oxidation may represent a protective strategy against irreversibleandmore dangerousformsof oxida-tion caused by high ROS levels. Accordingly,we have recentlyshownthat moderate,reversible oxidation pro-tectsthedopaminergicsysteminmultipleanimalmodels of PD[59].
Are
these
observations
important
for
PD?
Thiol/disulfide oxidation in normal conditions in SNpc dopamine neurons could beanexample of antagonistic pleiotropy, thatis atrait that isfavorable during repro-ductive stagesof life– for instanceto improve novelty-inducedexploration–andisthereforeunderevolutionary pressure,butbecomesdetrimentalduringaging[60,61]. Increased oxidation may provide the substrate for geneticandenvironmentalfactorstotrigger dopaminer-gicdegeneration.Moreover,someevidenceindicatesthat moderateoxidationmight beprotectivein PDand thus preservationoftolerablelevelofreversiblecysteine oxi-dation may constitute an experimental therapy worth exploring.
Conflict
of
interest
statement
Nothing declared.
Acknowledgments
PGMwaspartiallysupportedbyaTargetValidationgrantfromtheMichael J.FoxFoundation;CMwassupportedbyafellowshipfromtheFondazione Veronesi.
References
and
recommended
reading
Papersofparticularinterest,publishedwithintheperiodofreview, havebeenhighlightedas:
ofspecialinterest ofoutstandinginterest
1. FearnleyJM,LeesAJ:AgeingandParkinson’sdisease: substantianigraregionalselectivity.Brain1991, 114:2283-2301.
2. KleinC,WestenbergerA:GeneticsofParkinson’sdisease.Cold SpringHarbPerspectMed2012,2a008888.
3. ReedX,Bandres-CigaSetal.:Theroleofmonogenicgenesin idiopathicParkinson’sdisease.NeurobiolDis2019,
124:230-239.
4. LangstonJW,BallardPetal.:ChronicParkinsonisminhumans duetoaproductofmeperidine-analogsynthesis.Science 1983,219:979-980.
5. RamsayRR,DadgarJetal.:Energy-drivenuptakeof N-methyl-4-phenylpyridinebybrainmitochondriamediatesthe neurotoxicityofMPTP.LifeSci1986,39:581-588.
6. FahnS,CohenG:TheoxidantstresshypothesisinParkinson’s disease:evidencesupportingit.AnnNeurol1992,32:804-812.
7. JennerP:OxidativestressinParkinson’sdisease.AnnNeurol 2003,53(Suppl.3):S26-S36discussionS36-S28.
8. VarcinM,BenteaEetal.:Oxidativestressingeneticmouse modelsofParkinson’sdisease.OxidMedCellLongev2012, 2012:624925.
9. MartinezTN,GreenamyreJT:Toxinmodelsofmitochondrial dysfunctioninParkinson’sdisease.AntioxidRedoxSignal2012, 16:920-934.
10. WinterbournCC,HamptonMB:Thiolchemistryandspecificity inredoxsignaling.FreeRadicBiolMed2008,45:549-561.
11. ChintaS,AndersenJ:RedoximbalanceinParkinson’sdisease. BiochimBiophysActa2008,1780:1362-1367.
12. Garcia-GarciaA,Zavala-FloresLetal.:Thiol-redoxsignaling, dopaminergiccelldeath,andParkinson’sdisease.Antioxid RedoxSignal2012,17:1764-1784.
13. SbodioJI,SnyderSHetal.:Redoxmechanismsin neurodegeneration:fromdiseaseoutcomestotherapeutic opportunities.AntioxidRedoxSignal2019,30:1450-1499.
14. BetarbetR,ShererTBetal.:Chronicsystemicpesticide exposurereproducesfeaturesofParkinson’sdisease.Nat Neurosci2000,3:1301-1306.
15. McCormackAL,ThiruchelvamMetal.:Environmentalrisk factorsandParkinson’sdisease:selectivedegenerationof nigraldopaminergicneuronscausedbytheherbicide paraquat.NeurobiolDis2002,10:119-127.
16.
GuzmanpacemakingJN,Sanchez-PadillaindopaminergicJetneuronsal.:OxidantisattenuatedstressevokedbyDJ-1.by Nature2010,468:696-700.
Thisstudyusesaredoxsensitivefluorescentproteintodeterminethe glutathioneredoxstateindopaminergicneuronsatsinglecellleveland shows that dopaminergic neurons in the substantia nigra are more oxidizedthanthoseintheventraltegmentalarea.
17. HansonGT,AggelerRetal.:Investigatingmitochondrialredox potentialwithredox-sensitivegreenfluorescentprotein indicators.JBiolChem2004,279:13044-13053.
18. GutscherM,PauleauALetal.:Real-timeimagingofthe intracellularglutathioneredoxpotential.NatMethods2008, 5:553-559.
19. LilligCH,HolmgrenA:Thioredoxinandrelatedmolecules— frombiologytohealthanddisease.AntioxidRedoxSignal2007, 9:25-47.
20. HanschmannEM,GodoyJRetal.:Thioredoxins,glutaredoxins, andperoxiredoxins—molecularmechanismsandhealth significance:fromcofactorstoantioxidantstoredox signaling.AntioxidRedoxSignal2013,19:1539-1605.
21. TrotterEW,GrantCM:Non-reciprocalregulationoftheredox stateoftheglutathione-glutaredoxinandthioredoxin systems.EMBORep2003,4:184-188.
22. MastroberardinoPG,OrrALetal.:AFRET-basedmethodto studyproteinthioloxidationinhistologicalpreparations.Free RadicBiolMed2008,45:971-981.
23.
HorowitzdemonstratesMP,MilaneseadistinctiveCetresponseal.:Single-cellofdopaminergicredoximagingneurons tooxidativeinsults.AntioxidRedoxSignal2011,15:855-871.
This study uses fluorescent labeled maleimide derivatives to label reducedandoxidizedcysteinesandtomeasuretheglobalthiol/disulfide redox state. Thestudy shows atsingle cell level that dopaminergic neurons inthe substantianigra aremoreoxidized thanthose inthe ventraltegmentalarea.
24. TrepanierG,FurlingDetal.:Immunocytochemicallocalization ofseleno-glutathioneperoxidaseintheadultmousebrain. Neuroscience1996,75:231-243.
25. HungHC,LeeEH:MPTPproducesdifferentialoxidativestress andantioxidativeresponsesinthenigrostriataland mesolimbicdopaminergicpathways.FreeRadicBiolMed1998, 24:76-84.
26. HookPW,McClymontSAetal.:Single-cellRNA-Seqofmouse dopaminergicneuronsinformscandidategeneselectionfor sporadicParkinsondisease.AmJHumGenet2018, 102:427-446.
27. GriffithsPD,DobsonBRetal.:Ironinthebasalgangliain Parkinson’sdisease.AninvitrostudyusingextendedX-ray absorptionfinestructureandcryo-electronmicroscopy.Brain 1999,122:667-673.
28.
SurmeierParkinsonDJ,disease.ObesoJANatetReval.:SelectiveNeurosci2017,neuronal18:101-113.vulnerabilityin
AcomprehensivereviewprovidinganexcellentoverviewonParkinson’s diseasepathogenesis.Thearticlealsoincludesacleardescriptionof cell-autonomousfactors,specificfordopamineneuronsthatmaybe respon-sibleforPDpathogenesis.
29. PutzierI,KullmannPHetal.:Cav1.3channelvoltage
dependence,notCa2+selectivity,drivespacemakeractivity andamplifiesburstsinnigraldopamineneurons.JNeurosci 2009,29:15414-15419.
30. BranchSY,SharmaRetal.:AgingdecreasesL-typecalcium channelcurrentsandpacemakerfiringfidelityinsubstantia nigradopamineneurons.JNeurosci2014,34:9310-9318.
31. SchultzW:Multipledopaminefunctionsatdifferenttime courses.AnnuRevNeurosci2007,30:259-288.
32.
Bromberg-Martinmotivationalcontrol:ES,Matsumotorewarding,aversive,Metal.:Dopamineandalerting.inNeuron 2010,68:815-834.
Anexcellentreviewdiscussingmidbraindopaminergicneurons physiol-ogyunderabehavioralperspective.
33. RiceME,PatelJCetal.:Dopaminereleaseinthebasalganglia. Neuroscience2011,198:112-137.
34. GraceAA,BunneyBS:Thecontroloffiringpatterninnigral dopamineneurons:burstfiring.JNeurosci1984,4:2877-2890.
35. GraceAA,BunneyBS:Thecontroloffiringpatterninnigral dopamineneurons:singlespikefiring.JNeurosci1984, 4:2866-2876.
36. SchultzW:Predictiverewardsignalofdopamineneurons. JNeurophysiol1998,80:1-27.
37. ZweifelLS,ParkerJGetal.:DisruptionofNMDAR-dependent burstfiringbydopamineneuronsprovidesselective assessmentofphasicdopamine-dependentbehavior.Proc NatlAcadSciUSA2009,106:7281-7288.
38.
SchiemannsubstantiaJ,nigraSchlaudraffneuronsFcontroletal.:K-ATPburstingchannelsandnovelty-indopamine inducedexploration.NatNeurosci2012,15:1272-1280.
The study demonstrates that K-ATP channels gate burst firing the dopaminergic neurons of the substantia nigra and contribute to novelty-dependentbehavior.
39. KarschinC,EckeCetal.:OverlappingdistributionofK(ATP) channel-formingKir6.2subunitandthesulfonylureareceptor SUR1inrodentbrain.FEBSLett1997,401:59-64.
40. Aguilar-BryanL,ClementJPetal.:Towardunderstandingthe assemblyandstructureofKATPchannels.PhysiolRev1998, 78:227-245.
41. DragicevicE,SchiemannJetal.:Dopaminemidbrainneuronsin healthandParkinson’sdisease:emergingrolesof voltage-gatedcalciumchannelsandATP-sensitivepotassium channels.Neuroscience2015,284:798-814.
42. YamadaK,JiJJetal.:ProtectiveroleofATP-sensitive potassiumchannelsinhypoxia-inducedgeneralizedseizure. Science2001,292:1543-1546.
43. YamadaK,InagakiN:NeuroprotectionbyKATPchannels.JMol CellCardiol2005,38:945-949.
44. SoundarapandianMM,ZhongXetal.:RoleofK(ATP)channelsin protectionagainstneuronalexcitatoryinsults.JNeurochem 2007,103:1721-1729.
45.
AvshalumovperoxideregulatesMV,ChentheBTexcitabilityetal.:Endogenousofmidbrainhydrogendopamine neuronsviaATP-sensitivepotassiumchannels.JNeurosci 2005,25:4222-4231.
ThestudydemonstratedforthefirsttimethatK-ATPchannelsin dopa-mineneuronscanberegulatedbyendogenoushydrogenperoxide. 46.
dopamineAvshalumovpathwayMV,BaoviaLetATP-sensitiveal.:H2O2signalingpotassiuminthenigrostriatalchannels: issuesandanswers.AntioxidRedoxSignal2007,9:219-231.
An excellent review on H2O2 signaling, specifically in dopaminergic neurons.
47. CoetzeeWA,NakamuraTYetal.:Effectsofthiol-modifying agentsonKATPchannelsinguineapigventricularcells.Am JPhysiol1995,269:H1625-H1633.
48. JiangB,TangGetal.:MolecularmechanismforH(2)S-induced activationofK(ATP)channels.AntioxidRedoxSignal2010, 12:1167-1178.
49. LissB,BrunsRetal.:Alternativesulfonylureareceptor expressiondefinesmetabolicsensitivityofK-ATPchannelsin dopaminergicmidbrainneurons.EMBOJ1999,18:833-846.
50. LissB,HaeckelOetal.:K-ATPchannelspromotethe differentialdegenerationofdopaminergicmidbrainneurons. NatNeurosci2005,8:1742-1751.
51. JohnsonSW,SeutinVetal.:Burstfiringindopamineneurons inducedbyN-methyl-D-aspartate:roleofelectrogenicsodium pump.Science1992,258:665-667.
52. AizenmanE,LiptonSAetal.:SelectivemodulationofNMDA responsesbyreductionandoxidation.Neuron1989, 2:1257-1263.
53. BrimecombeJC,PotthoffWKetal.:Acriticalroleofthe N-methyl-D-aspartate(NMDA)receptorsubunit(NR)2Ainthe expressionofredoxsensitivityofNR1/NR2Arecombinant NMDAreceptors.JPharmacolExpTher1999,291:785-792.
54.
StockerperoxideS,signalingVanLaerandKettheal.:emergingTheconundrumroleofperoxiredoxinsofhydrogen as redoxrelayhubs.AntioxidRedoxSignal2018,28:558-573.
An interesting and comprehensive review on H2O2 mediated redox signalingpresentingelementsinfavorandagainstdirect or peroxire-doxin-mediatedmodificationofcysteinesbyH2O2.
55. MarinhoHS,RealCetal.:Hydrogenperoxidesensing,signaling andregulationoftranscriptionfactors.RedoxBiol2014, 2:535-562.
56.
SobottaredoxrelayMC,forLiouH2WO2etsignaling.al.:Peroxiredoxin-2NatChemBioland2015,STAT311:64-70.forma
Thestudydemonstratesaredoxsignalingmechanism,inwhichH2O2 mediatedproteinmodificationistransducedbyperoxiredoxin.
57. GoY-M,ChandlerJDetal.:Thecysteineproteome.FreeRadic BiolMed2015,84:227-245.
58. vanderReestJ,LillaSetal.:Proteome-wideanalysisof cysteineoxidationrevealsmetabolicsensitivitytoredox stress.NatCommun2018,9:1581.
59. MilaneseC,TapiasVetal.:MitochondrialcomplexIreversible S-nitrosationimprovesbioenergeticsandisprotectivein Parkinson’sdisease.AntioxidRedoxSignal2018,28:44-61.
60. WilliamsGC:Pleiotropy,naturalselection,andtheevolutionof senescence.Evolution1957,11:398-411.
61. KirkwoodTB:Understandingtheoddscienceofaging.Cell 2005,120:437-447.
