Insights into The Pathogenesis Of Neurodegenerative Disease: Focus On Mitochondrial Dysfunction Thiab Oxidative Stress Part 3
Jul 16, 2024
4.3.3. DNA
ROS tuaj yeem ua rau muaj ntau hom DNA puas, xws li kev hloov pauv hauv paus, deoxyribosemodification, ib leeg-strand so (SSBs) thiab ob-strand so (DSBs), DNA crosslinks, lossis abasic sites [235].
Raws li peb kawm paub ntau ntxiv txog biology, peb tab tom pom tias kev hloov pauv hauv paus tuaj yeem cuam tshuam rau tib neeg kev nco. Lub tswv yim no zoo siab heev vim nws txhais tau tias peb tuaj yeem siv cov kev hloov kho no los txhim kho thiab txhim kho peb lub hlwb ua haujlwm.
Cov kev tshawb fawb tau pom tias ntxiv methylation rau exon DNA tuaj yeem cuam tshuam kev nco tsim thiab muaj peev xwm kawm spatial. Hauv tib neeg lub hlwb cov qauv, DNA puag 5-Hydroxymethylcytosine (5hmC) tau raug txheeb xyuas thiab nws cov lus qhia hauv tib neeg lub hlwb cortex cheeb tsam tau nce.
Kev tshawb fawb ntxiv tau pom tias kev tau txais cov ntaub ntawv tshiab thiab sib sau ua ke yuav tsum muaj tsawg kawg yog ob lub hlwb sib txawv, xws li "sau" thiab "kev tsim tawm". Hauv lub sijhawm kaw, cholinergic neurons tso acetylcholine hloov cov ntaub ntawv los ntawm lub sijhawm luv mus rau lub sijhawm ntev. Hauv cov txheej txheem no, methylase (DNA methyltransferase) ua lub luag haujlwm tseem ceeb vim tias nws tuaj yeem ua lub luag haujlwm tseem ceeb hauv kev tswj cov noob qhia thaum muaj kev nco tshiab.
Nyob rau hauv lub tom ntej no theem, lub reproduction theem, neurons replay yav dhau los yaam puab paub. Qhov no txhais tau hais tias lub cim xeeb sib sau tau muab tso rau hauv lub cim xeeb ntev, thiab qee cov kws tshaj lij ntseeg tias cov tshuaj methylation ntawm cov noob no tau hloov mus rau ib daim ntawv uas yooj yim heev rau thim rov qab, xws li 5-Hydroxymethylcytosine. Ntawd yog, yutian acid plays lub luag haujlwm tseem ceeb hauv kev sib koom ua ke kev nco mus ntev.
Yog li ntawd, peb tuaj yeem pom tias kev hloov pauv hauv paus thiab kev nco zoo sib xws. Qhov no ua rau peb muaj kev cia siab zoo los tsim qee cov kev kho mob tshiab los txhim kho lub hlwb kev ua tau zoo, xws li kev paub txog kev txawj ntse, thiab tsis txhob muaj kev txawj ntse. Txawm hais tias tseem muaj ntau txoj haujlwm yuav tsum tau ua, qhov no yog ib qho ntawm cov kev tshawb fawb ntawm peb txoj kev nkag siab thiab tshawb nrhiav ntau lub paj hlwb. Nws tuaj yeem pom tau tias peb yuav tsum txhim kho kev nco, thiab Cistanche tuaj yeem txhim kho kev nco zoo vim Cistanche tuaj yeem tswj hwm qhov sib npaug ntawm cov neurotransmitters, xws li nce qib ntawm acetylcholine thiab kev loj hlob yam, uas tseem ceeb heev rau kev nco thiab kev kawm. Tsis tas li ntawd, Cistanche tseem tuaj yeem txhim kho cov ntshav khiav thiab txhawb nqa cov pa oxygen, uas tuaj yeem ua kom lub hlwb tau txais cov khoom noj txaus thiab lub zog, yog li txhim kho lub hlwb tseem ceeb thiab kev ua siab ntev.
Oxidized DNA yog tej zaum feem ntau DNA lesionin neurons [236]. Raws li ib txwm muaj, ROS tuaj yeem ua rau 50, 000 DNA lesions / cell / hnub [237], thiab qeeb hauv kev kho DNA puas tuaj yeem ua rau genomic instability thiab induce signaling cascades ua rau cell tuag [238].
Cov hlwb muaj ntau yam kev kho, xws li lub hauv paus excision kho (BER), kev kho tsis zoo (MMR), nucleotide excisionrepair (NER), thiab ib leeg- (SSBR) thiab kho ob-strand break (DSBR) mechanisms [239].
Oxidized DNA bases raug tshem tawm feem ntau los ntawm BER / SSBR mechanism thiab koom nrog kev tshem tawm ntawm lub hauv paus puas los ntawm ib qho DNA glycosylase (DG), incision ntawm qhov chaw abasic los ntawm AP-endonuclease (APE1), sau qhov sib txawv ntawm DNApolymerase. , thiab sealing ntawm cov DNA puas strand los ntawm ib tug DNA ligase [240].
Ntau DGs tau raug txheeb xyuas, xws li uracil-DNA glycosylases (UDGs), thymine DNA glycosylase (TDG), lossis oxidized base-specific DGs, xws li 8-oxoGuanine (8-oxoG) DNAglycosylase (OGG1) [ 241, 242] ib. OGG1-1a yog koom nrog hauv kev kho DNA nuclear, thaum OGG1-2a pab txhawb rau mitochondrial DNA kho [243].
APE1 cleaves qab zib-phosphatebackbone ntawm DNA ntawm qhov chaw abasic. Phosphorylation ntawm enzyme, raws li tshwm sim tom qab 1-methyl-4-phenylpyridinium (MPP+) raug, txo nws cov enzyme kev ua si thiab ua rau tsub zuj zuj ntawm puas DNA nyob rau hauv neurons [244].
Mitochondrial DNA yog qhov ua rau oxidative puas tsuaj vim tias mitochondrial genome nyob ze rau ntawm IMM, qhov chaw ntawm mitochondrial ROS tiam, thiab vim nws tsis muaj kev tiv thaiv histones [245]. Raws li mitochondrial DNA tswj zoo yog qhov tseem ceeb rau kev sib txuas lus nrog lub nucleus, mitochondria muaj antioxidant thiab DNArepair enzymes, xws li OGG1 thiab MUTYH (mutY DNA glycosylase) [246].
Mitochondrialdysfunction, raws li tshwm sim tom qab mtDNA tshem tawm, tuaj yeem ua rau kev ua haujlwm ntawm NF- κB los ntawm acalcineurin-dependent signaling pathway [247] thiab tuaj yeem ua rau muaj kev cuam tshuam los ntawm ntau lub cim taw qhia. Piv txwv li, PPAR-coactivator 1 thiab SIRT1 tswj mitochondrialfunction los ntawm kev ua kom cov lus qhia ntawm mitochondrial transcription factor A (TFAM) [248].
Ntxiv nrog rau kev puas tsuaj oxidative ntau ntxiv los ntawm oxidative kev nyuaj siab, cov txheej txheem DNArepair puas tau raug piav qhia hauv cov kab mob neurodegenerative, xws li AD lossis PD [235].
Dopaminergic neurons ntawm PD cov neeg mob tau qhia txog kev tswj hwm ntawm mitochondrialOGG1 thiab qib siab ntawm phosphorylated APE1 [249]. Neurons los ntawm cov neeg mob AD muaj qib siab dua ntawm oxidized DNA hauv paus hauv nuclear nrog rau mitochondrial DNA [250], pom qhov txo qis ntawm OGG1 kev ua haujlwm [251], thiab qis dua UDG [252] piv nrog cov neurons los ntawm cov neeg noj qab haus huv.
4.3.4. RNA thiab Oxidative Damage
RNA muaj ntau dua, suav txog 80-90% ntawm cov nucleic acid hauv hlwb [253], thiab muaj kev cuam tshuam rau oxidative puas tsuaj vim nws cov qauv ib leeg, nyob sib ze rau lawv, tsis muaj oxidized RNA kho mechanisms, thiab kev tiv thaiv tsawg dua los ntawm proteinsas piv rau DNA [60,254].
Kev ua haujlwm ntawm RNA molecules hauv cell muaj ntau haiv neeg, suav nrog ribosomal RNA (rRNAs), uas ua ke nrog kev hloov pauv RNA (tRNA) thiab xa xov RNA (mRNA) yog lub luag haujlwm rau kev tsim cov protein, microRNAs (miRNAs), uas yog tom qab kev txhais lus. regulators ntawm noob qhia, thiab me me nuclear thiab nucleolarRNAs.
Kev lig kev cai, mRNA raug suav hais tias yog coding RNA [255]. Cov tsis-coding RNAs ua lub luag haujlwm tseem ceeb hauv mRNA splicing regulation thiab mRNA translation [256].Qhov kev txhoj puab heev tshaj plaws yog cov hydroxyl radical, uas tsim nyob rau hauv Fenton thiab Haber-Weiss cov tshuaj tiv thaiv [257].
Nws reacts nrog guanine los tsim 8-hydroxyguanosine (8-OHG), yog ib qho ntawm feem ntau siv biomarkers ntawm RNA oxidation [253]. Lub oxidative attack-induced kev puas tsuaj rau RNA ua rau hloov pauv hauv paus thiab nucleosides, cleavage, thiab fragmentation ntawm tRNA, aminoacylation, los yog tsis xws luag nyob rau hauv codon-anticodon pairing [258] thiab ua rau ncaj qha RNA strand breaks [259], lub hauv paus mismatches ntawm tRNAs, txhais lus yuam kev [182], and disordered protein synthesis [260] nrog rau kev cuam tshuam tseem ceeb ntawm cell viability.
Txawm hais tias cov cell muaj ntau lub tswv yim los ua kom cov ntaub ntawv hloov pauv, xws li tsis muaj tseeb-mediatedmRNA decay (NMD) [261], cov txheej txheem no yuav dhau los ua kev laus. Raws li, hloov pauv misfolded proteins sib sau [262].
5. Selective Neuron Vulnerability nyob rau hauv Cov Kab Mob Neurodegenerative
Txawm hais tias muaj ntau txoj hauv kev uas ua rau muaj kev nce ROS tiam thiab lawv cov txiaj ntsig siv rau txhua lub hlwb, txhua tus kab mob neurodegenerative ua rau cov degeneration ntawm cov pab pawg tshwj xeeb ntawm cov neurons, uas coj cov kws tshawb fawb los nrhiav cov lus piav qhia rau qhov kev xaiv qhov tsis zoo ntawm cov neeg neuronal.
5.1. Selective Neuronal Vulnerability nyob rau hauv Alzheimer's Disease
Kev nco thiab kev paub tsis meej ntawm AD yog tshwm sim los ntawm atrophyof lub endorhinal cortex (EC), feem ntau ntawm cov neurons hauv txheej II (ECII), thiab hippocampus, tshwj xeeb tshaj yog thaj tsam CA1 [72].
Kev tshawb fawb tau pom tias cov neurons hauv cov cheeb tsam no muaj kev xav tau ntau dua thiab muaj kev nkag siab zoo rau cov pa oxygen thiab qabzib tsawg [263]. Tsis tas li ntawd, CA1 thiab EC II pyramidal neurons yog glutamatergic thiab yog li muaj kev cuam tshuam ntau dua rau NMDA excitotoxicity thiab kev puas tsuaj ntawm cov calcium ntau ntxiv hauv cov cell [264], as opposed to neocortical inhibitory interneurons, uas muaj qib siab ntawm Ca{{3}6}5 binding proteins [264]. ].
Tsis ntev los no tau piav qhia txog cov cim ntawm cov cim molecular ntawm qhov tsis zoo neuronshave. Piv txwv li, ECII pyramidal neurons muaj qhov cuam tshuam tsis zoo ntawm tus tswj hwm ntawm tau splicing, zoo li txuas rau kev cuam tshuam microtubule dynamics [266], uas tuaj yeem pab txhawb tau kis mus rau lwm thaj chaw hauv hlwb ntawm CA1 neurons [267].
Selectivelyvulnerable excitatory neuron subpopulations tau qhia qhia RORB (RAR-relatedOrphan Receptor B), thaum tseem nthuav tawm qhov sib txawv ntawm kev qhia ntawm cov noob encodingsynapse- piv rau axon-localized proteins, subunits ntawm cov poov tshuaj raws, G-proteinsignaling molecules receptors, thiab neurotransmitters. [268].
Txawm li cas los xij, kev sib txuas ntawm RORB kev qhia, tsub zuj zuj ntawm phosphorylated tau, thiab neuraldegeneration tseem yuav tsum tau ua ntxiv.
5.2. Selective Neuronal Vulnerability nyob rau hauv Parkinson's Disease
Cov tsos mob ntawm lub cev muaj zog ntawm PD yog tshwm sim los ntawm kev poob ntawm nigral dopaminergic neurons ua rau dopamine depletion hauv dorsal striatum [269]. Raws li txoj cai, cov neuronshave ntev heev thiab branched axons (txog 4.5 m), tau txuas nrog ntau tus neurons (txog 2.4 lab synapses) [270,271], uas yuav tsum muaj qhov ntom ntom ntawm axonalmitochondria thiab cov nyom mitochondrial bioenergetics [272].
Ntawm qib molecular, nigral dopaminergic neurons muaj qis Ca2+-buffering peev txawm tias muaj kev ua haujlwm siab-nyob ntawm Ca2+ loads, uas ua rau OXPHOS thiab ROS tiam [273] thiab tuaj yeem txhawb kev puas tsuaj mtDNA [274]. Tsis tas li ntawd, cov metabolism ntawm dopamine nws tus kheej ua rau ROS tiam thiab ua rau cov tsub zuj zuj ntawm mtDNA deletions [275].
5.3. Lub cev muaj zog Neuron Vulnerability hauv Amyotrophic Lateral Sclerosis
Cov kab mob pathological ntawm ALS yog degeneration ntawm sab sauv thiab qis lub cev muaj zog neurons, uas ob leeg muaj axons ntev heev thiab, yog li, nyob ntawm kev ua haujlwm ntawm mitochondrial thiab kev lag luam [72].
Lub cev muaj zog loj loj ua rau muaj kev xav tau siab ntawm spinalmotor neurons los tswj cov neurotransmission thiab cov leeg nqaij [276].
Cov txheeb ze ntawm lub cev muaj zog neurons nyob rau hauv lub oculomotor, trochlear, thiab abducens nuclei tej zaum yuav txuas mus rau cov me me ntawm innervated nqaij fibers (txog tsib leeg nqaij fibers as opposedto tsawg kawg yog 300 fibers innervated los ntawm spinal motor neurons) [277], tshwj xeeb grape- zoo li cov qauv ntawm cov neuromuscular hlws ris [278], nrog rau siab Ca2+ buffering peev ntawm cov neurons [279].
6. Oxidative Stress nyob rau hauv cov kab mob Neurodegenerative
Kev tshawb fawb tau nce ntxiv pom tias muaj cov cim oxidative kev ntxhov siab nyob rau hauv lub paj hlwb ntawm cov neeg mob uas muaj kab mob neurodegenerative, tab sis txoj hauv kev molecular tsuas yog pib elucidated.
Cov lus piav qhia ntawm cov kab mob caj ces ua rau AD, PD, HD, lossis ALS tau pab txhawm rau txheeb xyuas cov teebmeem hauv qab ntawm cov proteins mutant, nrog rau txoj hauv kev zoo sib xws tau tshwm sim tom qab hauv cov kab mob idiopathic. Txawm li cas los xij, cov kab mob pathophysiology tseem tsis tau meej meej, txawm tias muaj kev paub ntau ntxiv tau coj mus rau kev sim kho.
6.1. Oxidative Stress nyob rau hauv Alzheimer's Disease
Cov neeg mob ntawm AD nrog kev hloov pauv ntawm Presenilin 1 (PS1) thiab 2 (PS2) tau txuas AD pathogenesis nrog cuam tshuam calcium homeostasis [280]. PSs cuam tshuam nrog ryanodine receptors [281] thiab cuam tshuam ER-mitochondria coupling [282].
Qhov tseeb, MAMnumbers siab tau piav qhia hauv cov qauv tsiaj ntawm AD thiab fibroblasts lossis cov ntaub so ntswg ntawm cov neeg mob AD [283]. Tsis tas li ntawd, A aggregates tuaj yeem kho Ca2+ hloov pauv ntawm ER mus rau lawv qhov chaw los ntawm MCU [284], thaum tau inhibits mitochondrial calcium efflux [285].
Ntxiv mus, A tuaj yeem tsim cov calcium-permeable raws hauv daim nyias nyias [286,287], thaum tau tuaj yeem tsim cov ion tsis xaiv hauv lipid bilayers [288]. Qhov cuam tshuam loj ntawm kev nce mitochondrial calcium nyob rau hauv inducing mitochondrial tsis ua hauj lwm thiab oxidative kev nyuaj siab tau piav nyob rau hauv lub dhau los seem.
Hauv astrocytes, Ib qho kev cuam tshuam nrog cov calcium-sensing receptors (CaSRs) induces lawv downregulation, ua rau cov neeg nyob sib ze neurons tosecrete tshiab synthesized A, nitric oxide, thiab peroxynitrite [289].
Hauv mitochondria, ib qho ntawm cov kev hloov pauv ntxov tshaj plaws uas txuas nrog AD yog epoxidation ntawm ATPsynthase nrog qhov txo qis ntawm nws txoj haujlwm, piav qhia hauv EC neurons thaum ntxov li Braak theem I-II [290,291]. Nyob hauv IMM, tso rau hauv PUFA-nplua nuj lipid bilayer, thiab ze rau ntawm mitochondrial matrix, enzyme yog lub hom phiaj yooj yim rau cov dawb radicals generated los ntawm complexes I thiab III [292].
Ntxiv nrog rau qhov tsis muaj zog, ATP synthase hloov kho ntxiv ua rau ROS ntau lawm nrog lub zog tom ntej ntawm oxidative kev hloov kho ntawm cov roj ntsha molecules [293].
Hauv qhov cascade no, cov khoom hloov pauv lipoxidation feem ntau koom nrog hauv cov metabolism hauv lub zog, ua kom lub zog tsis ua haujlwm, ua raws li cov proteins koom nrog hauv kev sib txuas, kev tiv thaiv antioxidant, thiab ion channels, raws li qhia hauv Table 1.
Kev sib txuas lus ntawm mitochondria thiab nucleus thiab kev ntshuam ntawm nuclear-coded mitochondrial subunits yog impaired los ntawm bioenergetic defects thiab dysfunctionalmitochondrial proteins, ua rau hloov kev qhia ntawm kev tswj thiab structural mitochondrial complexes thiab enzymes [299]. Cov lipid metabolism kuj hloov pauv, nrog rau kev hloov pauv hauv lipidomic profiles tau piav qhia hauv AD, tshwj xeeb hauv EC [300].
Cov oxidative puas tsuaj rau PUFAs ua rau txo cov fatty acids nyob rau hauv lipid rafts nyob rau hauv EC txij thaum ntxov ntawm AD [301], nrog rau txim ntawm daim nyias nyias thickness, fluidity, curvature, as well as kev ua ntawm daim nyias nyias cov proteins, uas txaus siab rau amyloidogenic ua ntawm amyloid. precursor protein.
Nws zoo nkaus li tias mitochondrial oxidative kev nyuaj siab, hloov lipidmetabolism, lipid peroxidation, thiab bioenergetic tsis xws luag yog tag nrho ib feem ntawm tus kheej-sustained loop uas pab txhawb rau augmentation ntawm cov hloov mitochondrial dynamics, mitochondrialtrafficking, impaired mitochondrial, thiab impaired mitochondrial.
Lub intracellular build-up ntawm amyloid beta (A) thiab phosphorylated tau inducesmuch ntawm cov hloov mitochondrial dynamics, qhia raws li ntau heev mitochondrial fragmentation, nrog ntau ntxiv thiab txo qhov loj ntawm mitochondria [302]. Ob leeg A thiab phosphorylated tau nce GTPase kev ua ntawm Drp1, uas ua rau ntau dhau mitochondrial fragmentation [303,304].
Hauv vitro, mutant APP cellular kab nthuav tawm highconcentrations ntawm mRNA thiab cov proteins ntawm mitochondrial fission thiab txo qis ntawm mRNA thiab cov proteins ntawm mitochondrial fusion [305]. Phosphorylated tau kuj tau qhia kom txo qis Opa1 thiab upregulate Mfn1 thiab Mfn2 [306].
Tsis tas li ntawd, cytoplasmic tsub zuj zuj ntawm A ua rau depletion ntawm Parkin thiab PINK1 qib, yog li cuam tshuam nrog txoj kev mitophagy. Kev puas tsuaj mitophagy tshwm sim hauv kev sib sau ntawm autophagicvacuoles nyob rau hauv neuronal soma thiab dysfunctional neurites [307], ib tug txheej txheem potentiated bythe tshwj xeeb ntawm mitophagy nyob rau hauv cov neurons, qhov twg mature lysosomes yog concentrated nyob rau hauv lub cell lub cev whereas mitochondria txuas mus rau lub axons ntawm neurons, mitophagy txheej txheem qeeb [308].
Tsis tas li ntawd, A oligomers cuam tshuam nrog autophagic vacuoles nyob rau hauv qhov chaw distal ntawm axons, ua rau inhibition ntawm mitochondrialaxonal thauj [309]. Tsis tas li ntawd, hauv cov qauv kuaj, kev hloov pauv hauv PS1 gene alteredlysosomal acidification [310] thiab coj mus rau qhov txo qis ntawm autophagy-related genesthrough ERK / CREB signaling pathway [311].
Protein tau kuj tseem muaj txiaj ntsig zoo rau kev tiv thaiv cellular genomein physiological mob, los ntawm kev khi chromatin [236]. Lub xeev hyperphosphorylated tau cuam tshuam nrog txoj haujlwm no, tsim cov chaw rau kev ua txhaum ntawm ntau oxidativeDNA kev puas tsuaj thiab lub sijhawm ntev yuav tsum tau kho cov kab mob DNA no [236].
Ib qho yuav tsum tsis txhob saib xyuas lub luag haujlwm ntawm kev ua kom microglial thiab mob o nyob rau hauv lub pathogenesis ntawm AD. Microglia, lub cev tiv thaiv kab mob macrophage zoo li cov hlwb ntawm lub paj hlwb, suav txog li 10% ntawm cov neeg hauv cellular hauv cov neeg laus noj qab haus huv hlwb [312].
Nyob rau hauv AD, microglia tau nce kev nthuav qhia ntawm kev sib ntxiv receptors ua rau kev txhim kho ntawm NF-κB kev taw qhia txoj hauv kev, A -activated Fc receptors (uas induces theexpression of MIP-macrophage inflammatory proteins -1 ), thiab nce kev nthuav qhia ntawm scavenger receptors A{ {4}} thiab B (SCARA thiab SCARB) [313,314]. Kev khi ntawm A rau SCARB-2 activates microglia, tsim cov proinflammatory cytokines, chemokines, thiab ROS [315].
Kev nce qib ntawm tau, los ntawm inducing cov kev qhia ntawm tus xov tooj hu-zoo li receptors, kuj ua rau muaj kev tso tawm ntawm pro-inflammatory cytokines IL-1 , IL-6, thiab IL-8 los ntawm NF-κB Txoj kev taw qhia [316]. Txawm hais tias qhov mob activates autophagy hauv hlwb [108], txij li qhov tsis zoo ntawm autophagy cuam tshuam rau cov hlwb microglial ib yam nkaus, cov kab mob inflammatory microglial phenotypes ntxiv ua rau muaj kev puas tsuaj rau neuronal hauv AD [317].
6.2. Oxidative Stress nyob rau hauv Parkinson's Disease
PD yog tus thib ob feem ntau cov kab mob neurodegenerative, nthuav tawm ob qho tib si kev txawj ntse thiab neuromuscular impairments.
Txawm hais tias feem ntau cov xwm txheej tsis sib xws, ntau qhov kev hloov pauv tau piav qhia hauv tsev neeg thiab cov ntawv pib ntxov ntawm PD, xws li kev hloov pauv hauv PARK1 (encoding PINK1), PARK2 (encoding for Parkin), PARK1/4 (-synuclein), PARK7 (DJ1), PARK8 (LRRK2), PARK9 (ATP13A2) PARK17 (Vsp35), FBX07, GIGYF2, los yog HTRA2, qhia txog kev koom tes ntawm ubiquitin protein degradation txoj kev, oxidative stress, cell survival pathway, mitochondrial function, thiab apopogenes 18.
Cov kab mob pathological ntawm PD yog qhov sib xyaw ntawm insoluble inclusions uas muaj feem ntau ntawm synuclein, (Lewy lub cev) feem ntau hauv cov nigral dopaminergic neurons [61].
Txoj kev tshawb fawb ntawm cov tshuaj lom neeg ua rau Parkinsonian syndromes tau pab hauv elucidating PDpathogenesis. Nyob rau hauv lub xyoo pua 20th, raug rau 1-methyl-phenyl 4-phenyl-1,2,3,6-tetrahydrpyridine tau pom tias ua rau cov tsos mob zoo li mob hnyav parkinsonism [319] los ntawm kev cuam tshuam. nrog complex I ntawm ETC.
Tsis tas li ntawd, hauv qhov chaw sim, rotenone, complexI inhibitor, ua rau apoptosis hauv tib neeg neuroblastoma hlwb, thiab qhov kev tshawb pom no tau nthuav dav los tham txog kev koom tes ntawm cov tshuaj tua kab hauv etiology ntawm PD [320].
Tom qab ntawd, ntau tus kws tshawb fawb tau qhia txog qhov tsis xws luag ntawm complex I ntawm mitochondrial ETC ua rau 30-40% poob rau hauv nws cov haujlwm [48,321], tshwm sim los ntawm kev txo qis ntawm kev tsim cov complex I subunits, kev puas tsuaj ntawm nws cov qauv, thiab oxidativedamage [ 322] ib. -synuclein lub hom phiaj mitochondria thiab ua rau txo qis hauv kev ua haujlwm nyuaj [323].
LLRK2 (leucine-nplua nuj rov kinase 2) kev hloov pauv tuaj yeem nce -synucleinlevels [324]. PINK1 thiab Parkin tswj mitophagy, raws li tau piav qhia ua ntej. DJ1 tseem ceeb rau mitochondrial kev ncaj ncees thiab dynamics; overexpression ntawm DJ1 tau pom tias yuav txo qis mitochondrial fragmentation tshwm sim los ntawm rotenone, ntawm tus kheej ntawm PINK1 [325].
Cov pov thawj ntseeg tau pom tias muaj ntau ntxiv ntawm lipid, protein, thiab DNAoxidation cov khoom lag luam hauv cov degenerating neurons hauv PD [326-328] ua ke nrog txo cov antioxidant GSH [329], yog li cuam tshuam oxidative kev nyuaj siab hauv pathogenesis ntawm PD.
Thaum pib, ROS tej zaum yog los ntawm ETC, lwm yam, thiab dopamineauto-oxidation [330], potentiated tom qab los ntawm monoamine oxidase B metabolism ntawm dopamine, inflammatory teb, los yog kev koom tes ntawm hnyav hlau [331].
ROS tau pom tias ua rau tsis muaj kev ua kom tsis muaj zog ntawm Iron Regulatory protein 1, yog li txhawb nqa toiron tsub zuj zuj hauv dopaminergic hlwb [332]. Hydrogen peroxide tuaj yeem yooj yim diffuse toadjacent neurons, qhov twg nws tuaj yeem tsim hydroxyl radicals los ntawm nws cov kev cuam tshuam nrog hlau [55].
PINK1 kev hloov pauv hauv kinase domain ntawm mitochondrially nyob molecule kuj ua rau cov hlwb ua rau muaj kev nyuaj siab oxidative [55,333].
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