Neuromelanin hauv Parkinson's Disease: Tyrosine Hydroxylase Thiab Tyrosinase Part 1
Apr 15, 2024
Abstract:
Parkinson's disease (PD) yog ib qho kab mob uas muaj feem cuam tshuam txog kev laus thiab yog tus kab mob neurodegenerative thib ob tom qab Alzheimer's disease. Cov tsos mob tseem ceeb ntawm PD yog kev txav mus los nrog kev tsis txaus ntawm cov neurotransmitter dopamine (DA) hauv striatum vim kev tuag ntawm tes ntawm nigrostriatal DA neurons.
Nyob rau hauv xyoo tas los no, ntau thiab ntau cov kev tshawb fawb tau pom muaj kev sib raug zoo ntawm kev txav mus los thiab kev nco. Tib neeg lub cim xeeb thiab kev txawj ntse tuaj yeem txhim kho los ntawm kev tawm dag zog kom tsim nyog, tab sis kev zaum ntev thiab tsis muaj kev tawm dag zog yuav cuam tshuam rau tib neeg lub paj hlwb thiab txawm ua rau kev txawj ntse poob qis, nco tsis muaj zog, thiab lwm yam teeb meem.
Ua ntej tshaj plaws, kev tawm dag zog tuaj yeem txhawb cov ntshav ncig hauv lub hlwb, yog li ua kom cov khoom noj khoom haus rau cov neurons, nce metabolism, thiab txhawb kev tsim cov neurons tshiab. Qhov kev txhim kho no tuaj yeem ua rau lub hlwb muaj peev xwm thiab hloov tau yooj yim thaum txhawb kev tsim thiab kho cov neural networks, yog li txhim kho tib neeg lub cim xeeb thiab kev txawj ntse.
Qhov thib ob, kev tawm dag zog kuj tuaj yeem txhawb lub cev cov ntshav ncig, thiab txhim kho lub cev metabolism thiab tiv thaiv kab mob, yog li txhim kho lub cev tiv thaiv thiab tiv thaiv kev tshwm sim ntawm ntau yam kab mob. Cov kab mob no tsis tsuas yog cuam tshuam rau tib neeg lub cev kev noj qab haus huv xwb tab sis kuj cuam tshuam rau lawv lub hlwb, txo lawv lub peev xwm thiab kev nco.
Tsis tas li ntawd, los ntawm kev tawm dag zog kom tsim nyog, tib neeg tuaj yeem tso siab rau lub cev thiab lub hlwb thiab txo cov kev xav xws li kev ntxhov siab, ntxhov siab, thiab kev nyuaj siab. Cov kev xav no yuav tsis tsuas yog cuam tshuam rau tib neeg lub siab lub ntsws tab sis kuj ua rau lub hlwb ua rau lub hlwb, cuam tshuam rau tib neeg lub cim xeeb thiab kev txawj ntse. Yog li ntawd, kev tawm dag zog kom zoo tuaj yeem txhawb kev noj qab haus huv ntawm lub cev thiab lub hlwb thiab txhim kho tib neeg txoj kev nco thiab kev muaj peev xwm kawm.
Hauv cov ntsiab lus, muaj kev sib raug zoo ntawm kev txav mus los thiab kev nco. Kev tawm dag zog kom zoo tuaj yeem txhawb nqa kev noj qab haus huv ntawm lub cev thiab lub hlwb, thiab txhim kho tib neeg txoj kev txawj ntse thiab kev nco. Yog li ntawd, peb yuav tsum koom nrog kev ua kis las thiab ua kom muaj kev noj qab haus huv hauv lub neej kom txhim kho peb lub cev thiab lub hlwb thiab lub neej zoo. Nws tuaj yeem pom tias peb yuav tsum txhim kho kev nco, thiab Cistanche deserticola tuaj yeem txhim kho kev nco zoo vim Cistanche deserticola yog cov khoom siv tshuaj hauv Suav teb uas muaj ntau yam teebmeem, ib qho ntawm kev txhim kho kev nco. Kev ua tau zoo ntawm Cistanche deserticola los ntawm ntau yam khoom xyaw uas nws muaj, suav nrog tannic acid, polysaccharides, flavonoid glycosides, thiab lwm yam. Cov khoom xyaw no tuaj yeem txhawb lub hlwb kev noj qab haus huv los ntawm ntau txoj hauv kev.
Nyem Paub txhawm rau txhim kho lub cim xeeb luv luv
Ob lub ntsiab lus histopathological muaj nyob hauv PD: cytosolic suav nrog lub cev hu ua Lewy lub cev uas feem ntau muaj -synuclein protein, cov oligomers uas tsim los ntawm misfolding yog suav tias yog neurotoxic, ua rau DA cell tuag; thiab blackpigments termed neuromelanin (NM) uas muaj nyob rau hauv DA neurons thiab markedly txo inPD.
Lub synthesis ntawm tib neeg NM yog suav hais tias zoo ib yam li melanin hauv melanocytes; melaninsynthesis nyob rau hauv daim tawv nqaij yog ntawm DOPAquinone (DQ) los ntawm tyrosinase, whereas NM synthesis nyob rau hauv DA neuronsis ntawm DAquinone (DAQ) los ntawm tyrosine hydroxylase (TH) thiab aromatic L-amino acid decarboxylase (AADC).
DA nyob rau hauv cytoplasm yog heev reactive thiab xav tias yuav oxidized spontaneously los yog anunidentified tyrosinase rau DAQ thiab ces, synthesized rau NM. Intracellular NM tsub zuj zuj saum toj ib qho kev qhia tshwj xeeb tau tshaj tawm tias cuam tshuam nrog DA neuron tuag thiab PD phenotypes.
Qhov kev tshuaj xyuas no qhia txog kev nce qib tsis ntev los no hauv biosynthesis thiab pathophysiology ntawm NM hauv PD.
Ntsiab lus:
dopamine; qhov chaw coeruleus; melanin; neuromelanin; norepinephrine; Parkinson tus kab mob; substantia nigra; tyrosinase; tyrosine hydroxylase.
1. Neuromelanin (NM) hauv Parkinson's Disease
Parkinson's disease (PD) yog tib neeg tshwj xeeb, kev loj hlob, kab mob ntsig txog kev laus, thiab thib ob feem ntau cov kab mob neurodegenerative tom qab Alzheimer's disease [1]. Xyoo 1817, James Parkinson hauv London tau luam tawm "Ib Daim Ntawv Qhia Txog Kev Ntxub Ntxaug", thawj qhov kev piav qhia txog kev kho mob ntawm tus kab mob tom qab hu ua Parkinson's disease. Cov tsos mob tseem ceeb ntawm PD yog cov tsos mob ntawm lub cev muaj zog, xws li tshee, bradykinesia, rigidity, thiab posturalinstability, nrog rau cov tsos mob uas tsis yog lub cev muaj xws li anosmia, cem quav, insomnia, REM-pw tsaug zog cwj pwm tsis zoo (RBD), ntxhov siab vim, kev nyuaj siab, qaug zog, kev txawj ntse. [1].
Feem ntau PD yog ib ntus tsis muaj keeb kwm ntawm tsev neeg (sPD). Tsuas yog 5-15 feem pua ntawm cov neeg mob yog tsev neeg PD (fPD) [2,3]. Lub pathophysiology ntawm PD tau tshawb xyuas los ntawm biochemicalanalysis ntawm post-mortem PD hlwb thaum nruab nrab ntawm lub xyoo pua 20th [4-7].
Txawm hais tias tus kab mob pathophysiology ntawm PD tseem tsis paub, sPD xav tias yog tshwm sim los ntawm kev sib xyaw ua ke ntawm ib puag ncig thiab caj ces. Cov tsos mob tseem ceeb ntawm PD, uas yog ib qho kev tsis sib haum xeeb, paub tias yog tshwm sim los ntawm kev txo qis hauv neurotransmitter dopamine (DA) nyob rau hauv lub striatum hauv basal ganglia vim neurodegeneration ntawm nigrostriatal DA neurons, thiab supplementation ntawm DA los ntawm tus thawj precursor L{ {0}}, 4-dihydroxyphenylalanine (L-DOPA) tseem yog tus qauv kub ntawm kev kho tshuaj ntawm PD tom qab tsib xyoos txij li xyoo 1970 [1,7,8].
L-DOPA kev kho mob muaj txiaj ntsig zoo rau kev txo qis ntau cov tsos mob tseem ceeb ntawm PD, tab sis nws tsis tiv thaiv kev loj hlob ntawm neurodegeneration thiab tom qab ntawd ua rau txo qis kev ua haujlwm thiab ntau yam kev mob tshwm sim xws li dyskinesia [7,8].
Kev tshawb pom ntawm cov noob caj noob ces ntawm ntau yam fPD, txij li thaum xaus ntawm lub xyoo pua 20th, tau txhawb nqa lub elucidation ntawm molecular mechanism ntawm sPD [3]; fPD yog lub npe nyob rau hauv qhov kev txiav txim ntawm nrhiav pom cov noob loci xws li PARK1 ( -synuclein, SNCA [9,10]) thiab PARK2 (parkin, PRKN [3,11,12]). Ntau tshaj 20 PARKs tau tshaj tawm.Cov ntawv luv PARK yog muab los ntawm lub npe PARKinson.
Kev hloov pauv hauv qee cov genesin fPD raug suav tias yog qhov ua rau thiab tseem cuam tshuam rau kev cuam tshuam loci hauv sPD, piv txwv, -synuclein gene (SNCA thiab PARK1) [9,10], parkin (PARK2) [3,11], PTEN-inducedputative kinase 1 (PINK1 thiab PARK6) [13,14], thiab leucine-nplua nuj rov kinase 2 (LRRK2 thiab PARK8) [15–18].
Muaj ob lub ntsiab lus histopathological hauv PD hauv degenerating nigrostriatalDA neurons, piv txwv li, Lewy lub cev thiab txo cov neuromelanin (NM) hauv substantia nigra (SN) (Daim duab 1): (1) Friedrich Heinrich piav txog cytosolic inclusion lub cev hu ua Lewy [19] 19] ib. Lewy lub cev muaj -synuclein protein raws li lub ntsiab protein tivthaiv, thiab cov fibrillar oligomers ntawm -synuclein protein ua los ntawm misfolding yog presumed rau beneurotoxic thiab ua rau DA cell tuag [20].
Kev hloov pauv ntawm -synuclein gene (SNCA) tau pom, xyoo 1997, ua rau muaj qhov tseem ceeb fPD (PARK1) uas degenerating dopamine neurons muaj ob lub cev Lewy uas muaj -synuclein thiab cov xim dub NM [9,10].
Rau cov laj thawj no, cov protein -synuclein tau raug tshuaj xyuas ntau hauv DA neurondeath hauv sPD. Txawm li cas los xij, cov lus nug ntxiv yog seb lub cev Lewy puas tau pom nyob rau hauv dominantfPD xws li PARK1 (SNCA), tab sis tsis yog nyob rau hauv recessive fPD xws li PARK2 (PARKIN). (2) Lub blackpigment NM, uas tau pom nyob rau hauv tib neeg SN, maj mam nce thaum lub sij hawm ib txwm laus hauv cov neeg noj qab haus huv [21].
NM yog nplua nuj nyob rau hauv lub hlwb ntawm tib neeg, tab sis nws muaj nyob rau hauv lub hlwb ntawm liab, nas, nas, dev, thiab nees [22,23]. Konstantin Tretiakoff [24], xyoo 1919, tau tshaj tawm tias NM tau txo qis hauv SN ntawm PD lub hlwb.
Kev txo qis hauv NM insome nigrostriatal DA neurons hauv SN pars compacta (SNpc), pom nrog lub qhov muag liab qab, yog lub ntsiab lus histopathological ntawm PD. Sib txawv ntawm Lewy lub cev, NM yog soj ntsuam sPD, dominant fPD, thiab recessive fPD.
NM kuj tseem muaj nyob rau hauv norepinephrine (NE) neurons nyob rau hauv tib neeg locus coeruleus (LC), qhov twg NE neurons kuj degenerate nyob rau hauv PD.In contrast to the -synuclein protein nyob rau hauv Lewy lub cev uas tau txais kev saib xyuas zoo, thebiosynthesis thiab pathophysiology ntawm NM hauv PD. nyob tsis paub. Ib qho laj thawj yog vim li cas qhov elucidation ntawm cov qauv tshuaj ntawm NM tau nyuaj vim muaj cov ntsiab lus me me tsuas yog hauv tib neeg lub hlwb tom qab.
Txawm li cas los xij, cov khoom siv tshuaj lom neeg thiab biosynthesispathway ntawm NM tau piav qhia nyob rau hauv ob lub xyoo dhau los raws li kev txhim kho cov tshuaj micro-kev tshuaj ntsuam xyuas ntawm NM cais tawm los ntawm SN ntawm lub hlwb tom qab lub hlwb [25–27], thiab pathophysiology ntawm NM muaj. kuj tau maj mam elucidated.
Daim duab 1. Ob lub cim histopathological hauv PD hauv nigrostriatal DA. Fibrillar oligomers tsim los ntawm misfolding yog suav tias yog neurotoxic thiab ua rau DA cell tuag.
Neuromelanin (NM) kuj muaj feem xyuam rau neurodegeneration thiab DA cell tuag vim NM attenuates oxidative stress rau neuroprotection. a-Syn, ib-synuclein; NM, neuromelanin; TH, tyrosine hydroxylase; AADCaromatic amino acid decarboxylase; ROS, reactive oxygen hom.
2. Biosynthesis ntawm Neuromelanin (NM): Tyrosine Hydroxylase thiab Tyrosinase
Cov pigmented NM hauv tib neeg SN tau kwv yees tau los ntawm DA thiab cysteine ntawm molar piv ntawm 2: 1 [27.
Nws tau raug tshaj tawm tias ntau yam catechol metabolites tau muab tso rau hauv NM hauv SN dopamine neurons thiab NE neurons hauv LC, tsim los ntawm oxidative deamination ntawm catecholamines los ntawm monoamine oxidase (MAO) thiab tom qab txo thiab oxidation los ntawm aldehyde dehydrogenase (ALDHand aldehyde reductase (ARDHand aldehyde reductase) ): DOPA, 3, 4-dihydroxyphenylacetic acid (DOPAC), thiab 3,4dihydroxyphenylethanol (DOPET) raws li dopamine metabolites; glycol (DOPEG) raws li NE metabolites [27-30](Daim duab 2).
Raws li cov txiaj ntsig no, txoj hauv kev ntawm NM biosynthesis ntawm DA oxidation toDAquinone (DAÃ) lossis NE oxidation rau NEquinone tau raug pom zoo kom zoo ib yam li melanin biosynthesis uas muaj txoj hauv kev ntawm DOPAquinone (DQ) hauv tib neeg daim tawv nqaij thiab plaub hau [31] .
Tsis tas li ntawd, nws tau pom zoo tias ntau yam catechol metabolites tau muab tso rau hauv NM, suav nrog DOPA, DOPAC, DOMA, DOPET, thiab DOPEG, uas yog cov metabolites ntawm DA thiab NE tsim los ntawm oxidative deamination los ntawm monoamine oxidase tom qab oxidation / los ntawm kev txo qis 29] (Daim duab 3).
Daim duab 2. Metabolism ntawm catecholamines. (DOPA) 3, 4-dihydroxyphenylalanine; (DA) dopamine; (NE) norepinephrine; (EN) epinephrine; (3-OMD) 3-O-methyldopa; (3MT) 3-methoxytyramine; (DOPAL) 3, 4-dihydroxyphenylacetaldehyde; (NMN) normetanephrine;(DOPEGAL) 3,4-dihydroxyphenylglycolaldehyde; (MN) metanephrine; (MOPAL) 3-methoxy4-hydroxyphenylacetaldehyde; (DOPAC) 3,4-dihydroxyphenylacetic acid; (DOPET) 3,4-dihydroxyphenylethanol; (MOPEGAL) 3-methoxy-4-hydroxyphenylglycolaldehyde; (DOMA)3,4-dihydroxymandelic acid; (DOPEG/DHPG) 3,4-dihydroxylphenylthyleneglycol/3,4-dihydroxyphenylglycol; HVA: homovanillic acid; MOPET: 3-methoxy-4-hydroxyphenylethanol; (VMA) vanillylmandelic acid; (MOPEG/MHPG) 3-methoxy-4-hydroxyphenylethyleneglycol/3-methoxy-4-hydroxyphenylgycol. (TH) tyrosine hydroxylase; (AADC) aromatic amino aciddecarboxylase; (DBH) dopamine- -hydroxylase; (PNMT) phenylethanolamine N-methyltransferase; (COMT) catechol-O-methyltransferase; (MAO) monoamine oxidase; (ALDH) aldehyde dehydrogenase; (AR) aldehyde reductase. Enzyme npe tau qhia nyob rau hauv italics rau lub hom phiaj ntawm clarity. Hloov kho los ntawm [28] nrog kev hloov kho me me.
Daim duab 3. Synthesis ntawm neuromelanin hauv SN lossis LC. Muaj peev xwm koom nrog ntau yam catecholaminemetabolites paub tias muaj nyob rau hauv ntau thaj tsam ntawm lub hlwb uas tuaj yeem muab tso rau hauv NMin substantia nigra (SN) lossis locus coeruleus (LC).
Ntxiv rau DA thiab NE thiab cov Cys derivatives sib raug zoo, cov lwm yam metabolites no kuj xav tias yuav muab tso rau hauv NM. (O) sawv cev rau oxidants. Noj
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