Neuromelanin hauv Parkinson's Disease: Tyrosine Hydroxylase Thiab Tyrosinase Part 3

Xwb, NM hauv DA neurons feem ntau tau raug suav hais tias ua yeeb yam rau kev tiv thaiv kab mob, txij li NM inactivates tshuaj lom dawb radical hom los ntawm nws lub peev xwm los chelate transitionmetals, tshwj xeeb tshaj yog hlau. Hlau kuj accumulates hauv DA neurons [112,115–117].

DA neurons yog ib hom neuron hauv lub hlwb uas feem ntau cuam tshuam nrog kev coj cwj pwm xws li khoom plig, kev saib xyuas, thiab kev txhawb siab. Txawm li cas los xij, raws li kev tshawb fawb txuas ntxiv mus, cov kws tshawb fawb tau tshawb pom tias DA neurons kuj tseem cuam tshuam nrog kev nco.

Cov kws tshawb fawb ib zaug pom nyob rau hauv cov kev sim nas uas ua kom DA neurons tuaj yeem txhim kho kev ua haujlwm ntawm cov nas hauv spatial thiab cov khoom paub txog cov haujlwm, uas qhia txog qhov cuam tshuam zoo ntawm DA neurons ntawm lub peev xwm nco. Tsis tas li ntawd, nyob rau hauv tib neeg, DA neurons kuj tau pom tias muaj feem cuam tshuam nrog kev tsim thiab kev saib xyuas ntawm kev nco, thiab tseem ua lub luag haujlwm tseem ceeb hauv kev kawm thiab kev txawj ntse.

Tshwj xeeb, DA neurons sib koom ua ke ntawm neural circuit hu ua "hippocampal-ventral 'VTA' cheeb tsam" (HP / VTA), uas tau xav tias muaj txiaj ntsig zoo rau kev nco thiab kev xav. Thaum ib tug neeg tab tom kawm tej yam tshiab, DA neurons tau qhib thiab tso cov tshuaj xws li dopamine los txhim kho kev kawm thiab txhim kho lub hlwb nco txog kev txhawb nqa. Qhov no yog vim li cas thaum koj kawm, koj yuav zoo siab thiab zoo siab, thiab nws kuj yog ib qho yooj yim rau nco ntsoov tej yam koj tau kawm.

Tsis tas li ntawd, kev tshawb fawb qhia tau hais tias DA neurons tseem tuaj yeem pab peb khaws cov ntaub ntawv zoo dua los ntawm kev tswj qhov muag saib, uas tseem hu ua "visually induced modulated memory." Cov kws tshawb fawb tau pom tias thaum peb ob lub qhov muag tshuaj xyuas cov khoom peb xav nco ntsoov, DA neurons tau qhib thiab pab peb khaws cov ntaub ntawv no zoo dua.

Nyob rau hauv luv luv, txawm hais tias lub luag hauj lwm ntawm DA neurons nyob rau hauv lub hlwb yog heev complex, nws cuam tshuam rau kev nco yog heev zoo thiab zoo. Yog li ntawd, peb yuav tsum tau saib xyuas peb cov neurons zoo thiab txhim kho peb lub cim xeeb thiab kev txawj ntse los ntawm kev kawm, kev tawm dag zog, thiab kev noj qab haus huv ntawm lub neej. Nws tuaj yeem pom tias peb yuav tsum txhim kho kev nco, thiab Cistanche deserticola tuaj yeem txhim kho kev nco, vim Cistanche deserticola tseem tuaj yeem tswj hwm qhov sib npaug ntawm cov neurotransmitters, xws li nce qib ntawm acetylcholine thiab kev loj hlob. Cov khoom no tseem ceeb heev rau kev nco thiab kev kawm. Tsis tas li ntawd, Cistanche deserticola kuj tseem tuaj yeem txhim kho cov ntshav khiav thiab txhawb nqa cov pa oxygen, uas tuaj yeem ua kom lub hlwb tau txais cov as-ham txaus thiab lub zog, yog li txhim kho lub hlwb tseem ceeb thiab kev ua siab ntev.

Nyem Paub Short-term Nco yuav ua li cas txhim kho

Hlau yog boundto NM nyob rau hauv ferrous (II) hlau daim ntawv, ib tug redox-active daim ntawv uas yog koom nyob rau hauv ib tug Fenton-likereaction los tsim tshuaj lom dawb radical hom. NM kuj tshem tawm ntau yam tshuaj lom hauv cytoplasm.

Yog li, NM tuaj yeem ua rau neuroprotection kuj hauv vivo. Txawm li cas los xij, thaum lub sij hawm kev vam meej ntawm PD, kev tso tawm cov tshuaj lom neeg khi rau NM vim yog intracellular NMdegradation tuaj yeem ua rau kev ua kom cov microglia tso tawm cytotoxic cytokines uas tsim neuroinflammation thiab neurodegeneration [78,118]. PD tshwm sim spontaneously rau tib neeg.

Txhawm rau tsim cov PD phenotype hauv ntau cov qauv ntawm PD hauv cov tsiaj txhu xws li cov kab mob thiab nas uas yuav luag tsis muaj NM hauv lub hlwb, nws yog ib qho tsim nyog los ua rau DA neurodegeneration los ntawm qee cov tshuaj lom neeg xws li 1-phenyl-4- methyl-1,2,3,6-tetrahydropyridine (MPTP) uas inhibits mitochondrial complex I [97].

Vila pawg tau tshaj tawm tias NMaccumulation hauv DA neurons thaum lub sijhawm laus dhau qhov pib ua rau DA neuron tuag thiab PD phenotype [119–121]. Lawv tsim tus qauv nas ntawm tib neeg PD los ntawm kev tshaj tawm ntawm tib neeg NM hauv txoj cai SNpc los ntawm kev txhaj tshuaj stereotaxic ntawm adeno-associated viral (AAV)vector qhia txog tib neeg tyrosinase [119].

Cov nas tau pom muaj hnub nyoog raws li kev tsim tawm ntawm tib neeg zoo li NM hauv nigral DA neurons, mus txog qib hauv cov neeg laus. Intracellular NMaggregation saum toj ib qho kev qhia tshwj xeeb yog txuam nrog lub hnub nyoog PD phenotype, suav nrog hypokinesia.

Txhim kho lysosomal proteostasis txo qis intracellular NM thiab tiv thaiv neurodegeneration hauv tyrosinase-overexpressing nas. Cov qib Intracellular NM tuaj yeem tsim qhov pib rau qhov pib ntawm PD. Tsis tas li ntawd, extracellular NM leaked los ntawm deadNM-muaj DA neurons yuav qhib microglia los tsim neuroinflammation thiab ntxiv txhawb DA cell tuag [122].

NM yog tus neeg sib tw kub los ua rau PD thiab / lossis ua rau muaj kev loj hlob ntawm PD, txawm li cas los xij, muaj cov teeb meem tsis daws teeb meem tshwm sim los ntawm kev kho mob ntawm PD nrog levodopa: (1) Cov ntaub ntawv tom qab tuag tsis tau pom tias nce NM hauv kev muaj sia nyob. NM uas muaj dopaminergic neurons ntawm SN tom qab levodopa kev kho mob ntev thiab (2) kev kho mob ntev ntev tsis tau pom tias muaj kev nce ntxiv ntawm PD.

NM txoj kev xav yog qhov haum rau phenotypes ntawm tib neeg sPD. Tsis tas li ntawd, muaj ntau yam pov thawj ntawm cytotoxicity ntawm -synuclein [10,19,123].

Tsis ntev los no, lub luag haujlwm ntawm NM hauv inducing -synuclein kev qhia thiab kev sib sau ua ke tau qhia tias yog lub tswv yim rau cov xim no los hloov kho cov teeb meem neuronal hauv PD [124]. -Synuclein reacts nrog tyrosinase, thiab cov tshuaj hloov kho ntawm tyrosinase-kho -synuclein cuam tshuam nws cov khoom sib sau ua ke thiab ua kom muaj tshuaj lom, thiab -synuclein tuaj yeem cuam tshuam cov synthesis ntawm NM [125,126].

Hlau redox chemistry txhawb nqa kev sib sau ntawm -synuclein, thiab cov protein-hlau complex aggregates ncaj qha koom nrog ROS ntau lawm, exacerbating oxidative puas tsuaj [127]. Tsis tas li ntawd, DA neurons yooj yim qhia MHC-I, thiab induction ntawm MHC-I yog txhawb los ntawm kev ua kom microglia los ntawm -synuclein los yog NM, nrog rau los ntawm interferon-gamma lossis siab cytosolic DA thiab oxidativestress [128].

Cov activated microglia hauv PD lub hlwb qhia cov histocompatibility complexclass II (MHC-II) molecules. Tus naj npawb ntawm MHC-II zoo microglia hauv SN thiabputamen nce ntxiv raws li cov neuronal degeneration ntawm SN tau mus [129].

Ib qho kev hloov pauv txoj kev xav tau raug npaj los piav qhia tib neeg tshwj xeeb PD raws li kev loj hlob ntawm tib neeg lub paj hlwb cortex dua li ntawm basal ganglia [130–132]. Clinically, PD yog ib qho kab mob, thiab nws nyuaj rau piav qhia txog cov txheej txheem degenerative, tshwj xeeb tshaj yog nyob rau hauv lub paj hlwb, tshwj xeeb tshaj yog los ntawm NM txoj kev xav, txawm hais tias muaj pov thawj tias cov kab mob ntawm PD yog qhov nyuaj thiab cuam tshuam nrog kev mob hlwb, oxidative stress, proteasomal. abnormalities, -synuclein tsub zuj zuj, alterations ntawm plab microbiota metabolites, thiab neuroinflammation [133,134]. Hauv cov ntsiab lus no, qhov kev hloov pauv ntawm qhov pom ntawm NM system thiab -synuclein system kuj yog qhov txaus siab.

4. Cov lus xaus

Neuromelanin (NM) yog xav kom ua ke los ntawm txoj kev hauv qab no: tyrosine → (TH) → DOPA → (AADC) → DA → (non-enzymatic oxidation lossis tyrosinase) → DAQ -- → euNM/pheoNM.

Nrhiav neuromelanin-specific tyrosinase (kev ua si) thiab DACtautomerase (kev ua si) tseem nyob rau yav tom ntej kev kawm raws li ib qho teeb meem tseem ceeb hauv pathophysiology ntawm PD. NM raug txiav txim siab ua ob qho tib si rau kev tiv thaiv neuroprotection thiab kev tuag ntawm tes ntawm DAneurons nyob ntawm cov qib intracellular ntawm tsub zuj zuj.

Lub pathophysiology ntawm NM txog -synuclein yog lwm qhov tseem ceeb rau kev qhia txog qhov ua rau PD.

Sau Kev Koom Tes: Kev xav, txhua tus kws sau ntawv; sau-original draft preparation, TN; sau-review and editing, KW, SI, HW thiab AN; visualization, KW, thiab AN Txhua tus neeg sau ntawv tau nyeem thiab pom zoo rau cov ntawv luam tawm ntawm cov ntawv sau.

Kev Kawm Txuj Ci: Qhov kev tshawb fawb no tsis tau txais nyiaj txiag sab nraud.

Institutional Review Board Statement: Tsis siv tau.

Cov Lus Qhia Txog Kev Pom Zoo: Tsis siv tau.

Cov Lus Qhia Muaj Cov Ntaub Ntawv: Tsis siv tau.

Kev tsis sib haum xeeb ntawm kev txaus siab: Cov neeg sau ntawv tshaj tawm tsis muaj teeb meem ntawm kev txaus siab.

Cov ntawv luv

Cov ntaub ntawv

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