Lub luag hauj lwm ntawm TOMM40'523' Polymorphism nyob rau hauv kab mob txaus ntshai thiab hnub nyoog ntawm cov tsos mob tshwm sim nyob rau hauv ob qho tib si Parkinson tus kab mob Cohorts

Abstract

Kev ua haujlwm tsis zoo ntawm mitochondrial yog cov txheej txheem tseem ceeb hauv kev tsim cov kab mob Parkinson's disease (PD). Lub hauv paus pore-forming protein TOM40 ntawm lub mitochondria yog encoded los ntawm lub translocase ntawm sab nrauv mitochondrial membrane 40 homolog noob (TOMM40). Qhov sib txawv heev '523' poly-T rov hais dua yog cuam tshuam nrog lub hnub nyoog txog kev paub txog kev poob qis thiab hnub nyoog pib ntawm Alzheimer's kab mob, tab sis seb nws ua lub luag haujlwm hauv kev hloov kho qhov kev pheej hmoo lossis kev kho mob ntawm PD tseem tsis tau piav qhia. TOMM40 '523' allele ntev tau txiav txim siab hauv 634 tus neeg nrog PD thiab 422 kev tswj hwm kev noj qab haus huv los ntawm Australian pawg neeg sib tw thiab Parkinson's Progression Markers Initiative (PPMI) pawg, siv cov tshuaj tiv thaiv polymerase saw lossis tag nrho genome sequencing tsom xam. Genotype thiab allele frequencies ntawm TOMM40 '523' thiab APOE ε tsis txawv ntawm cov pawg. Kev soj ntsuam tau qhia TOMM40 '523' pawg allele tsis cuam tshuam nrog kev pheej hmoo kis mob thaum xav txog APOE ε genotype. Regression analytics qhia txog TOMM40 S/S genotype tau cuam tshuam nrog lub hnub nyoog tom qab ntawm cov tsos mob tshwm sim hauv PPMI PD pawg, tab sis tsis yog tom qab kho rau covariates, lossis hauv Australian pawg. Txawm hais tias qhov kev hloov pauv hauv TOMM40 '523' polymorphism tsis cuam tshuam nrog PD kev pheej hmoo, qhov ua tau tias nws yuav yog qhov hloov pauv rau hnub nyoog ntawm cov tsos mob tshwm sim tau lees paub ntxiv kev tshawb nrhiav hauv lwm cov neeg PD.

Nyem qhov no kom paubcov txiaj ntsig ntawm Cistanche

Taw qhia

Parkinson's disease (PD) tau paub ntau ntxiv tias yog ib qho kev puas siab puas ntsws ntau yam nrog rau cov tsos mob tshwm sim thiab ua rau muaj kev mob tshwm sim. Kev ua haujlwm tsis zoo lossis tsis txaus mitochondrial yog qhov cuam tshuam dav raws li cov txheej txheem tseem ceeb hauv kev xaiv neuronal kev tuag thiab pathogenesis ntawm PD. Mitochondrial dysfunction, uas ua rau poob ntawm electron thauj saw (ETC) efficiency los yog poob rau hauv ATP-synthesising muaj peev xwm, zoo li elicit dopaminergic cell tuag los ntawm ob peb mechanisms, nrog rau reactive oxygen hom (ROS) - tiam, impaired ATP ntau lawm, thiab cuam tshuam calcium. homeostasis. Lub luag haujlwm tseem ceeb ntawm mitochondrial dysfunction hauv PD yog txhawb nqa los ntawm ntau qhov kev ua haujlwm ntawm parkinsonism-ua rau co toxins, kev hloov caj ces, thiab retrotransposon insertions, uas tshwj xeeb cuam tshuam mitochondrial muaj nuj nqi. Kev pom los ntawm cov co toxins thiab kev hloov pauv no txhais tau hais tias mitochondrial dysfunction nyob rau hauv lub pathogenesis ntawm PD tuaj yeem tshwm sim los ntawm ntau cov txheej txheem lom neeg, xws li kev cuam tshuam ntawm bioenergetic, nuclear thiab mitochondrial DNA hloov pauv, tsis zoo fusion thiab fission, mitophagy tsis zoo, qhov txawv txav, thiab qhov loj me. Piv txwv li, ib qho tseem ceeb ua rau mitochondrial dysfunction nyob rau hauv PD yog qhov inhibition ntawm mitochondrial complex I, ib qho ETC tsis xws luag uas ua rau mob oxidative kev nyuaj siab thiab ROS- thiab caspase-mediated dopaminergic cell tuag. Qhov tseem ceeb, qhov kev puas tsuaj tom kawg yog qhov tseem ceeb ntawm cov kab mob PD tshwm sim los ntawm tsev neeg PTEN-induced kinase 1 (PINK1), alpha-synuclein (SNCA), thiab Daisuke-Junko-1 (DJ-1) noob hloov. los yog cov tshuaj lom 1-methyl-4-phenyl-1,2,3,{16}} tetrahydropyridine (MPTP). Yog li, mitochondrial dysfunction yog xav tias yuav ua rau neuronal kev nyuaj siab thiab degeneration, tshwm sim nyob rau hauv no neurodegenerative kab mob, PD.

Lub translocase ntawm sab nrauv mitochondrial membrane 40 homologs (TOMM40) gene encodes lub pore-forming subunit (TOM40) ntawm cov protein-transport channels nyob rau hauv lub mitochondrial txheej membrane, yog li ua lub luag haujlwm tseem ceeb hauv kev ua haujlwm mitochondrial. Te TOM40 protein pab txhawb kev ntshuam ntawm kwv yees li 1500 cov khoom siv sab nraud thiab cov peptides rau hauv mitochondria thiab ua lub luag haujlwm tseem ceeb hauv txoj kev mitophagy degradation. Hloov lossis ua haujlwm txawv txav TOM40, kho los ntawm kev hloov pauv caj ces lossis kev qhia cov protein atypical, xav tias yuav pab txhawb rau mitochondrial dysfunction thiab protein ntau ntxiv hauv Alzheimer's kab mob (AD) thiab PD. Qhov no yuav tshwm sim los ntawm cov txheej txheem sib txawv: (1) mitochondrial ntshuam impairment, uas yuav tiv thaiv cov proteins thiab peptides tseem ceeb los ntawm kev ncav cuag lawv lub hom phiaj mitochondrial, los yog tso cai rau cov tsis xav tau thiab mutant proteins sib sau ua ke hauv mitochondria; los yog (2) mitophagy cuam tshuam, uas yuav ua rau puas thiab malfunctioning mitochondria mus sau. Muab cov pov thawj rau mitochondrial dysfunction nyob rau hauv PD, genetic variants cuam tshuam rau TOMM40 qhia tej zaum yuav muaj kev pheej hmoo thiab kab mob-hloov cov teebmeem.

Qhuav CistanchethiabCistanche ntsiav tshuaj

Hauv qab ntawm TOMM40 yog apolipoprotein E (APOE), uas yog nyob rau hauv ib cheeb tsam ntawm kev sib txuas tsis sib haum xeeb (LD), los yog tsis sib xws, nrog TOMM40 variation. Txawm hais tias qhov ntau npaum li cas ntawm qhov sib txawv hauv TOMM40 tuaj yeem muaj APOE-kev ywj pheej cuam tshuam ntawm kev pheej hmoo ntawm tus kab mob lossis kev hloov kho kab mob tseem tsis tau paub meej, polymorphisms hauv TOMM40 tau ua rau nws tus kheej cuam tshuam nrog ntau yam kev paub txog kev paub txog cov kab mob neurodegenerative, suav nrog AD, frontotemporal dementia, thiab dementia nrog Lewy lub cev, nrog rau cov laus uas tsis yog-pathological. Ib qho ntawm cov kev hloov no yog nyob rau hauv intron 6 ntawm TOMM40 thiab yog homopolymer ntawm rov ua thymine (T) nucleotides hu ua rs10524523 lossis '523'. Lub '523' variant yog polymorphic, nrog ntev uas txawv ntawm 11 txog 39 T residues hauv Caucasians. Txhawm rau kom zoo dua categorize thiab piav qhia txog qhov sib txawv ntawm cov qauv no, peb pawg allelic rau homopolymer tau raug tsim los ua ntej, raws li tus naj npawb ntawm T residues: 'Short' (S, T Tsawg dua lossis sib npaug rau 19), 'Long' (L , 20 Less tshaj los yog sib npaug T Less tshaj los yog sib npaug rau 29) thiab 'Nyob ntev' (T Greater los yog sib npaug rau 30). Txawm hais tias qhov kev ua haujlwm ntawm '523' kev hloov pauv feem ntau tsis paub, qhov ntev ntawm poly-T rov ua dua yog xav kom nce TOMM40 qhia. Yog li, cov nyhuv ntawm TOMM40 '523' txawv thiab hloov pauv TOM40 cov protein ntau tuaj yeem ua rau mitochondrial tsis ua haujlwm hauv PD. Txawm hais tias muaj ntau qhov kev tshawb fawb luam tawm qhia txog kev tsis sib haum xeeb ntawm ntau yam TOMM40 '523' qhov sib txawv ntawm qhov ntev hauv AD thiab cov neeg laus, tsuas muaj ob qhov kev tshawb fawb dhau los hauv PD pawg nrog cov kev tshawb pom sib txawv. Thawj yog ib qho kev tshawb fawb ntawm Polish PD cohort loj heev uas pom tsis muaj kev koom tes tseem ceeb ntawm TOMM40 '523' thiab PD kev pheej hmoo lossis hnub nyoog pib. Tom qab ntawd, qhov tseem ceeb tshaj tawm ntawm L / VL '523' genotype tau tshaj tawm hauv Swedish PD pawg piv rau kev tswj hwm kev noj qab haus huv, txawm hais tias nws yuav tsum tau muab sau tseg tias cov kev tshawb pom no tseem tsis tau luam tawm tag nrho. Yog li, nrog kev pom tsis sib haum xeeb hauv ob pawg neeg European no, kev tshawb nrhiav ntxiv hauv lwm cov pej xeem yog xav tau.

Vim yog lub luag haujlwm tseem ceeb ntawm TOMM40 hauv mitochondrial ntshuam thiab mitophagy, ob qho tib si plausible qhov chaw ntawm PDcausing mitochondrial dysfunction, '523' variant nyob rau hauv TOMM40 yog, yog li ntawd, muaj peev xwm muaj feem cuam tshuam thiab hloov kho kab mob hauv PD. Txoj kev tshawb no tshawb xyuas qhov kev faib tawm ntawm '523' alleles thiab lawv cov koom haum nrog kev pheej hmoo ntawm kab mob thiab hnub nyoog ntawm cov tsos mob tshwm sim hauv ob pawg PD ywj pheej, ib tus neeg Australian thiab ib qho thoob ntiaj teb (Parkinson's Progression Markers Initiative, PPMI), siv PCR-based thiab tag nrho cov genome sequencing. txoj hauv kev.

Kev sib tham

Txoj kev tshawb fawb tam sim no tsom los tshawb xyuas TOMM40 '523' cov qauv sib txawv raws li qhov muaj peev xwm PD muaj feem cuam tshuam thiab hloov kho lub hnub nyoog ntawm cov tsos mob tshwm sim. Kev faib tawm ntawm '523' poly-T alleles tsis txawv ntawm PwP thiab kev tswj hwm kev noj qab haus huv, lossis hauv ob pawg neeg ywj pheej tau tshuaj xyuas. Qhov zoo sib xws hauv '523' allelic faib ntawm PPMI thiab Australian pawg yog tsim nyog sau cia raws li txoj kev tshawb no tau siv ob txoj hauv kev sib txawv hauv kev hu rau TOMM40 '523' variant, tsim kom muaj PCR-raws li thiab WGS-raws li kev soj ntsuam siv rau hauv Australian thiab PPMI cohorts, feem. Kev ntsuam xyuas kev txhim kho rau TOMM40 '523' variant feem ntau suav hais tias yog qhov nyuaj, vim tias poly-T variants yog qhov nyuaj rau kev ua ntu zus. Txawm hais tias kev ua kom zoo nyob rau hauv txoj kev tshawb no, PCR stuttering tau pom nyob rau hauv PCR-raws li kev soj ntsuam zoo ib yam li cov ntaub ntawv dhau los, uas yog tus qauv teeb meem thaum ua kom rov ua cov genomic sequences, thiab qhia txog qhov yuav tsum tau ua kom zoo ntxiv ntawm qhov kev ntsuam xyuas. Los ntawm kev sib piv, hu xov tooj los ntawm WGS cov ntaub ntawv tau nthuav tawm qhov kev faib tawm zoo ib yam li tau tshaj tawm yav dhau los. Thaum nws tau raug nthuav tawm tias muaj kev sib tw tsawg dua hauv kev ua kom zoo dua qub thiab sib luag, kev hu xov tooj ntawm '523' sib txawv yog cov txheej txheem nyuaj thiab txoj kev tshawb no tau hais tias qhov kev sib raug zoo ntawm '523' hu los ntawm WGS thiab PCR-raws li txoj kev txo qis nrog qhov loj ntawm ua '523'.

Cistanche tubulosa

Txoj kev tshawb fawb tam sim no tau tshuaj xyuas seb qhov TOMM40 '523' variant puas cuam tshuam rau PD kev pheej hmoo thiab pom tsis muaj kev sib koom ua ke ntawm cov khoom sib txawv ntawm cov khoom sib txawv thiab kev pheej hmoo ntawm kev tsim PD. Thaum binned, genotypic thiab allelic zaus tshwm sim zoo ib yam ntawm kev tswj hwm thiab PwP hauv ob pawg neeg ywj pheej, thiab thaum cov pawg sib koom ua ke. Qhov no pom zoo nrog kev ua haujlwm yav dhau los hauv Polish PD pawg uas tsis pom muaj kev koom tes ntawm '523' alleles, genotypes, lossis haplotypes nrog kev pheej hmoo ntawm PD lossis hnub nyoog ntawm cov tsos mob tshwm sim. Nyob rau hauv sib piv, nyob rau hauv ib tug Swedish pej xeem, ntau zaus ntawm L / VL genotype tau pom nyob rau hauv cov neeg mob PD piv rau kev tswj, txawm tias cov kev tshawb pom no tseem tsis tau luam tawm tag nrho. Muab hais tias cov kev tshawb fawb no tau ua nyob rau hauv ntau haiv neeg, thiab hais tias '523' allele frequencies yog haiv neeg tshwj xeeb, qhov kev tsis sib haum xeeb ntawm cov kev tshawb fawb txog niaj hnub no yuav qhia tau tias '523' yog ib qho kev pheej hmoo ntawm qee cov neeg, tab sis tsis nyob rau lwm tus. Raws li qhov no tsuas yog qhov thib peb txoj kev tshawb fawb los tshawb xyuas lub luag haujlwm ntawm TOMM40 '523' hauv PD kev pheej hmoo, kev tshawb fawb ntxiv yuav tsum tau ua nyob rau hauv lwm haiv neeg.

Raws li kev koom tes ntawm mitochondrial hauv PD yog xav tias yog ib qho tseem ceeb rau kev ua haujlwm ntawm lub paj hlwb thiab kev degeneration, nws yog plausible tias ib hom kab mob sib txawv uas hloov kho mitochondrial muaj nuj nqi tuaj yeem hloov kho lub hnub nyoog ntawm cov tsos mob tshwm sim. Tsis tas li ntawd, AD thiab PD qhia ntau yam kev kho mob, kab mob, thiab cov yam ntxwv ntawm molecular nrog rau cov protein ntau ntxiv thiab mitochondrial dysfunction nyob rau hauv daim ntawv ntawm kev ua pa tsis xws luag, oxidative kev nyuaj siab, mitochondrial DNA puas, thiab morphological abnormalities. Cov kev tshawb fawb yav dhau los tau cuam tshuam txog TOMM40 '523' ntev hauv lub hnub nyoog pib ntawm AD, tshwj xeeb tshaj yog nyob rau hauv cov neeg nqa khoom ntawm APOE ε3 allele, tab sis kev tshawb pom sib xyaw muaj nyob. Piv txwv li, txawm tias Roses et al. tshaj tawm tias ntev '523' allele ntev tau cuam tshuam nrog kev pheej hmoo ntawm AD thiab lub hnub nyoog ntxov ntawm qhov pib, qhov kev tshawb pom thawj zaug tsis tau rov ua dua rau lwm tus neeg. Cov kev tshawb pom sib txawv no tuaj yeem yog los ntawm cov txheej txheem sib txawv thiab cov kev xav sib txawv ntawm qhov cuam tshuam ntawm APOE ε locus, uas yog tsim tau zoo raws li qhov muaj zog tshaj caj ces kwv yees ntawm AD. Feem ntau cov kev tshawb fawb txog niaj hnub tshaj tawm tsis muaj kev koom tes ntawm APOE ε variation nrog susceptibility rau PD, ib yam li cov ntaub ntawv nyob rau hauv txoj kev tshawb no tam sim no. Txawm hais tias qhov kev tshawb pom tam sim no tsis tau pom muaj pov thawj zoo ntawm kev sib tham sib cuam tshuam ntawm TOMM40 '523' thiab APOE ε genotypes txog PD kev pheej hmoo, lawv tau hais tias ob loci yuav muaj kev ywj pheej me me thiab cuam tshuam rau kev txiav txim siab hnub nyoog pib ntawm cov tsos mob. Thaum qhov kev ntsuam xyuas thawj zaug hauv pawg PPMI tau pom tias lub hnub nyoog pib tau qeeb qeeb los ntawm kev thauj mus los ntawm S / S '523' genotype, qhov no tsis tau rov ua dua tom qab kho rau covariates, lossis hauv Australian pawg. Txawm li cas los xij, qhov sib txawv no yuav tshwm sim los ntawm lub teb chaws- lossis thaj chaw tshwj xeeb, raws li pom hauv lwm cov kev tshawb fawb caj ces. Nws yog ib qho tsim nyog sau cia tias tsuas yog ib qho kev tshawb fawb ua ntej tau tshuaj xyuas lub koom haum no, txawm hais tias nws tsis paub meej tias qhov kev tshawb fawb no tau ua tiav qhov kev soj ntsuam nruj ntawm kev sib cuam tshuam ntawm TOMM40 thiab APOE, raws li tau ua hauv txoj kev tshawb fawb tam sim no. Yog li ntawd, kev soj ntsuam ntxiv hauv qhov tob hauv cov pawg PD loj dua yuav tsum tau txiav txim siab qhov tseem ceeb ntawm qhov kev tshawb pom tam sim no.

Tam sim no, cov kev ua haujlwm ntawm kev hloov pauv hauv '523' allele ntev tsis to taub vim qhov tsis txaus ntawm kev tshawb fawb hauv cheeb tsam no. Txawm hais tias ntau qhov kev tshawb fawb tau qhia tias VL allele nce TOMM40 mRNA qhia thiab S allele represses qhia, lwm tus tau pom tsis muaj qhov sib txawv tseem ceeb hauv mRNA qib ntawm S thiab VL variants. Ib txoj kev tshawb fawb tsis ntev los no tau pom tias kev nthuav tawm ntau dhau ntawm TOMM40 hauv vitro tau cuam tshuam nrog ntau dua mitochondrial membrane muaj peev xwm, tus nqi ua pa, ua pa muaj peev xwm ua pa, ATP qib, amyloid-beta tsis kam, thiab protein uptake. Ntawm qhov tod tes, lwm txoj kev tshawb fawb tau pom muaj kev sib raug zoo ntawm TOM40 cov protein tsis txaus thiab txhim kho oxidative kev nyuaj siab, txo qis ATP ntau lawm, thiab qhov txawv txav ntawm I protein ntau hauv lub hlwb ntawm cov neeg mob PD thiab alpha-synuclein overexpressing murine qauv. Raws li cov ntaub ntawv tam sim no sawv, ntxiv elucidation ntawm cov txiaj ntsig lom neeg ntawm kev nce lossis txo qis-tswj TOMM40 kev qhia yuav tsum tau muab kev pom rau nws lub luag haujlwm tseem ceeb hauv PD kev pheej hmoo thiab kev hloov kho kab mob.

Cistanche cov teebmeem

Xaus

Zuag qhia tag nrho, txoj kev tshawb no tsom los tshawb xyuas qhov kev pheej hmoo thiab kab mob-hloov lub luag haujlwm ntawm TOMM40 '523' variant hauv ob pawg PD ywj pheej. TOMM40 ua lub luag haujlwm tseem ceeb hauv mitochondrial ntshuam thiab mitophagy, thiab '523' polymorphism tau cuam tshuam nrog lub hnub nyoog pib ntawm AD thiab nrog hnub nyoog txog kev paub txog kev poob qis. Thaum txoj kev tshawb fawb no qhia meej tias TOMM40 '523' tsis yog nyob rau hauv nws tus kheej qhov kev kwv yees ntawm PD kev pheej hmoo, nws nce qhov muaj peev xwm, xws li hauv AD, nws yuav yog tus cim caj ces rau lub hnub nyoog ntawm cov tsos mob tshwm sim hauv PD. Txawm hais tias tsis yog qhov tseeb, peb qhov kev tshawb pom hauv lub ntiaj teb loj PPMI pawg qhia tias kev thauj mus los ntawm S / S '523' genotype tuaj yeem tiv thaiv kev ncua hnub nyoog ntawm cov tsos mob tshwm sim, thiab tuaj yeem lav kev tshawb nrhiav ntxiv rau lwm tus neeg. Qhov tseem ceeb, cov txiaj ntsig ntawm kev sib koom ua ke ntawm APOE ε4 allele, uas zoo li muaj kev cuam tshuam rau lub hnub nyoog pib, yuav tsum tau txiav txim siab hauv kev tshawb fawb yav tom ntej. Txawm hais tias tsis yog qhov tseem ceeb hauv kev hloov pauv qhov kev pheej hmoo ntawm PD, cov kev tshawb fawb yav tom ntej yuav tsum xav txog lub luag haujlwm ntawm TOMM40 '523' raws li qhov kev txiav txim ntawm lub hnub nyoog ntawm cov tsos mob tshwm sim, thiab cov tsos mob trajectory. Muab rau theem 3 kev soj ntsuam ntawm kev kho mob rau kev tiv thaiv thiab ncua ntawm qhov pib ntawm AD tsis ntev los no tau ua los ntawm cov neeg koom nrog stratified los ntawm TOMM40 '523'46, qhov kev tshawb pom tau qhia hauv no yog qhov tseem ceeb thiab tuaj yeem tso cai rau kev tsim cov tsos mob-kev tshawb fawb hauv PD rau xav tau kev txhim kho ntau yam ntawm tus neeg mob cov txiaj ntsig thiab kev saib xyuas.

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Megan C. Bakeberg 1,2, Madison E. Hoes 1, Anastazja M.Gorecki 1,3, FrancesTheunissen 1,4, Abigail L. Pfaf 1,4, Jade E. Kenna 1,2, Kai Plunkett 1, Sulev Kõks 1 ,4, P.AnthonyAkkari 1,2,4, Frank L. Mastaglia 1,2,4 & Ryan S.Anderton 1,2,5.

1. Perron Institute for Neurological and Translational Science, Nedlands, WA, Australia.

2. Center for Neuromuscular and Neurological Disorders, University of Western Australia, Nedlands, WA, Australia.

3. School of Biological Sciences, University of Western Australia, Crawley, WA, Australia.

4. Lub Chaw Kho Mob Molecular thiab Innovative Therapeutics, Murdoch University, Murdoch, WA, Australia.

5. Lub Tsev Haujlwm Saib Xyuas Kev Noj Qab Haus Huv thiab Tsev Kawm Ntawv Kev Noj Qab Haus Huv, University of Notre Dame Australia, 19 Mouat Street, Fremantle, WA 6959, Australia.