Lub luag haujlwm ntawm MicroRNAs hauv Proteostasis poob thiab Protein Aggregation

Thov hu rauoscar.xiao@wecistanche.comyog xav paub ntxiv

Abstract:Kev laus tuaj yeem txhais tau tias yog qhov ua kom tsis zoo ntawm cov cellular, cov ntaub so ntswg, thiab cov kab mob ua haujlwm hauv lub sijhawm. Kev hloov pauv hauv cov protein homeostasis, tseem hu ua proteostasis, yog lub cim ntawm kev laus uas ua rau muaj qhov tsis txaus ntawm cov protein thiab cov protein sib sau ua ke, tshwm sim uas tshwm sim hauv cov kab mob muaj hnub nyoog. Ntawm ntau yam kev tswj hwm proteostasis, microRNAs (miRNAs) tau tshaj tawm los ua lub luag haujlwm tseem ceeb hauv kev tswj hwm cov noob caj noob ces koom nrog kev tswj hwm proteostasis thaum lub sijhawm ua neej nyob hauv ntau cov ntaub so ntswg. Hauv kev tshuaj xyuas no, peb sib sau ua ke tsis ntev los no cov ntaub ntawv tshaj tawm uas qhia tau tias yuav ua li cas miRNAs tswj cov txheej txheem tseem ceeb ntawm cov txheej txheem proteostasis cuam tshuam rau cov ntaub so ntswg laus, nrog rau qhov tseem ceeb ntawm ob feem ntau cov ntaub so ntswg, cov ntaub so ntswg hlwb, thiab cov leeg pob txha. Peb kuj tseem tshawb nrhiav qhov kev pom tshwm sim ntawm lub luag haujlwm ntawm miRNA kev tswj hwm kev sib txuas hauv cov hnub nyoog ntsig txog cov protein sib sau ua ke, paub txog cov cim ntawm kev laus thiab cov kab mob uas muaj hnub nyoog, kom paub meej cov neeg muaj peev xwm miRNA sib tw rau kev tiv thaiv kev laus thiab kho cov hom phiaj.

Thov nias ntawm no kom paub ntxiv

Ntsiab lus:miRNA; mammalian cov ntaub so ntswg aging; muaj hnub nyoog txog cov protein sib sau ua ke; proteostasis network

1. Taw qhia

Los ntawm 2050,22 feem pua ​​​​ntawm lub ntiaj teb cov pej xeem yuav muaj hnub nyoog tshaj 60 xyoo, uas yuav ua rau muaj kev nce ntxiv ntawm cov kab mob uas muaj hnub nyoog thiab cuam tshuam rau lub neej ntev thiab kev noj qab haus huv ntawm cov neeg laus [1]. Kev hloov pauv hauv proteostasis yog cov yam ntxwv ntawm cov hnub nyoog cuam tshuam nrog cov kab mob neurodegenerative zoo li Alzheimer's thiab Parkinson's, thiab tseem muaj kev laus li qub [2-4]. Proteostasis poob qis muaj qhov tsis sib xws hauv cov protein synthesis, folding, thiab degradation txheej txheem nyob rau lub sij hawm uas ua rau kom muaj protein ntau misfolding thiab proteotoxic kev nyuaj siab uas thaum kawg txo cov kab mob mus ntev [2,5-8].

Cistanche tuaj yeem tiv thaiv kev laus

Kev tsim cov misfolded proteins ua rau cov protein sib sau ua ke thiab ua kom muaj kev cuam tshuam txog kev ntxhov siab, uas yog hu ua proteostasis network (PN) thiab koom nrog cov lus teb thaum tshav kub kub (HSR), cov lus teb ntawm cov protein ntau hauv endoplasmic reticulum ( ER) (UPREN) thiab hauv mitochondria (UPRmt), ubiquitin-proteasome system (UPS), thiab autophagy-lysosomal pathway (ALP). Kev ua kom PN yog tsim nyog los rov ua dua thiab / lossis txo qis cov protein ntau, uas txo qis kev ntxhov siab thiab tiv thaiv kev tuag ntawm tes [9-12]. Protein aggregation thaum lub sij hawm laus laus kuj tau kawm nyob rau hauv ntau lub cev qauv, uas yog nyob rau hauv lub raum thiab pancreas ntawm Rattus norvegicus [13,14], nyob rau hauv lub plawv, pob txha pob txha, thiab spleen ntawm Musculus [15,16], thiab nyob rau hauv lub plawv. tib neeg cortex[17,18]. Txawm li cas los xij, lub hauv paus mechanisms ntawm qhov tshwm sim no tseem tsis meej txog hnub no.

MicroRNAs (miRNAs) yog ib chav kawm me me, uas tsis yog-coding RNAs 21 txog 23 nucleotides ntev uas tswj cov gene qhia post-transcriptionally los ntawm lub hom phiaj thiab tiv thaiv kev txhais lus ntawm cov tub txib tshwj xeeb RNAs (mRNA). Lawv tswj hwm ntau cov txheej txheem ntawm tes, uas yog kev loj hlob ntawm tes thiab kev sib txawv, kev loj hlob hauv lub cev, kev ua haujlwm ntawm lub cev, thiab cell homeostasis [19-21]. Qhov tseeb, qhov ~ 2500 miRNAs qhia nyob rau hauv tib neeg tswj kwv yees li 60 feem pua ​​​​ntawm cov protein-coding noob, thaum txhua tus miRNA tswj, qhov nruab nrab, 200 lub hom phiaj cov noob los ntawm cov phiaj xwm ntxiv [22]. Tshaj li kaum xyoo dhau los, miRNA overexpression thiab/los yog knockdown thwmsim tau pom tau hais tias ncaj qha hloov lifespan hauv C.elegans, D.melanogaster, thiab M.musculus[23-26]. Qhov tseem ceeb, cov kev tshawb fawb hauv centenarians tau muab kev paub ntau ntxiv txog yuav ua li cas tib neeg miRNA profiles muaj zog thoob plaws hauv kev laus [27,28] Piv txwv li, nce biogenesis ntawm miRNAs tau pom nyob rau hauv centenarians piv nrog octogenarians [29]. Cov kev tshawb fawb tsis ntev los no tau pom tias miRNAs tswj cov txheej txheem muaj hnub nyoog, thiab qee cov pov thawj txuas miRNAs rau cov protein sib sau ua ke hauv cov ntaub so ntswg tsiaj, xws li hauv lub hlwb thiab cov leeg pob txha [30,31].

Txawm li cas los xij, miRNA kev qhia tuaj yeem yog cov ntaub so ntswg tshwj xeeb lossis cov xovtooj ntawm tes, thiab tib lub sijhawm, miRNAs tuaj yeem ua haujlwm tsis yog lub xovtooj ntawm tes, ua tus neeg nruab nrab ntawm ntau cov ntaub so ntswg [32]. Kev hloov pauv hnub nyoog uas cuam tshuam rau cov tsev neeg miRNA tshwj xeeb yuav txawv raws li hom cell thiab cov ntaub so ntswg, ua rau cov kev tshuaj ntsuam no nyuaj vim qhov nyuaj thiab kev sib cuam tshuam ntawm miRNA tes hauj lwm hauv ib lub cev [19,26]. Tsis tas li ntawd, circulating miRNAs (c-miRNAs) thiab lawv cov shuttles (piv txwv li, extracellular vesicles) tsis ntev los no tau sau tseg tias yog cov cim ntawm kev noj qab haus huv lub cev laus, nrog miR-19a-3p thiab miR-19 b-3p pom tias muaj kev nce ntxiv hauv cov neeg laus tab sis txo qis hauv cov neeg noj qab haus huv centenarians, yog li ntxiv lwm txheej ntawm intricacy rau miRNA kev tswj hwm network[27,28]. Vim li no, cov kev tshawb fawb yav dhau los tau muab tso ua ke ntawm miRNAs cuam tshuam nrog cov cim kev laus hauv ntau hom kab mob los muab kev sawv cev zoo dua ntawm miRNAs uas txuas rau kev laus hla ntau cov ntaub so ntswg [33]. Qhov kev tshuaj xyuas no tsom mus rau cov ntaub ntawv tshaj tawm tsis ntev los no ntawm miRNA kev tswj hwm ntawm cov noob hom phiaj koom nrog hauv cov txheej txheem proteostasis uas cuam tshuam rau cov ntaub so ntswg laus, nrog rau tshwj xeeb rau cov ntaub so ntswg laus.

2. Biogenesis thiab Target Binding ntawm miRNAs

RNA polymerase II transcribes miRNAs, tsim thawj miRNA transcripts (ua ntej-miRNAs) uas tom qab ntawd ua tiav los ntawm Drosha/DGC8, ib qho RNase III enzyme microprocessor complex, los tsim ~ 70-100 nucleotide (nt) stem-loop precursor miRNAs (pre -miRNAs) [21,34]. Cov pre-miRNAs no raug xa tawm los ntawm cov nucleus mus rau hauv cytoplasm ntawm Exportin-5, ib qho RanGTP-dependent, ob-stranded RNA-binding thiab nuclear-transport protein, thiab ces cleaved los ntawm RNase II enzyme Dicer, yielding {{ 13}}nt ob-stranded mature miRNA duplexes [35,36]. Lub miRNA tuaj yeem tshwm sim los ntawm 5'sab ntawm qhov ua ntej. miRNA hu ua "5p" strand, lossis los ntawm 3'k kawg, uas yog hu ua "3p" strand [37] yav dhau los, cov txheej txheem ntawm kev xaiv strand tau tshaj tawm los pib nrog ib qho ntawm cov duplexed miRNA strands hu ua miR los yog cov lus qhia strand, uas tau xaiv thiab thauj mus rau hauv Argonaute protein los tsim cov miRNA-induced silencing complex (miRISC), thaum lwm qhov strand, ib txwm denoted li cov neeg caij tsheb strand los yog miR', tau ejected ntawm complex thiab degraded [37 ]. Txawm li cas los xij, qee zaum, ob txoj hlua tuaj yeem raug xaiv thiab thauj mus rau hauv Argonaute cov proteins los tswj cov kev qhia gene, ib yam li cov ntaub ntawv ntawm miR-34 qhov twg miR-34b-5p thiab miR{ {27}}b-3p muaj nyob hauv kwv yees li qhov sib npaug ntawm tib neeg, tso cai rau lub hom phiaj ntawm mRNAs [37-39]. Qhov tshwm sim hu ua "miRNA caj npab hloov", yog qhov kev xaiv zoo tshaj plaws ntawm 3' lossis 5'miRNA caj npab rau kev xaiv strand tuaj yeem nyob ntawm hom ntaub so ntswg lossis nyob rau theem kev loj hlob ntawm lub neej, thaum lub de-regulation ntawm no. Cov txheej txheem cuam tshuam nrog cov kab mob [37-39]MiRISC tuaj yeem tsom rau mRNAs tshwj xeeb los ntawm kev sib txuas ua ke ntawm cov noob sib lawv liag ntawm cov khoom siv miRNA cov lus qhia strand (2-7 nucleotides) thiab feem ntau, 3 cheeb tsam tsis tau txhais lus (3 'UTR) ntawm lub hom phiaj mRNAs [32,34]. Qee qhov xwm txheej, 3' kawg ntawm miRNAs tuaj yeem tau txais qhov kev nyiam tshaj plaws los khi rau motifs hauv 5'UTR thaj tsam ntawm lub hom phiaj mRNAs[40,41]. Kev hloov caj npab tuaj yeem ua rau muaj qhov sib txuam ntawm mRNAs paub tab nrog cov noob hloov pauv, uas hloov pauv lub hom phiaj ntawm mRNAs[42] Thaum lub sijhawm laus, muaj kev hloov pauv dav dav hauv kev qhia ntawm 3 thiab 5'mature caj npab ntawm miRNAs, nrog nce 5. 'mature qhia thiab txo qis 3' qhia lub sijhawm, tshwj xeeb tshaj yog rau miR-6786 hauv tib neeg plasma kuaj [42]. Nyob rau tib lub sijhawm, miR-4423 tau txheeb xyuas nrog qhov txo qis tshaj 5' qhia piv txwv, xws li hauv cov kua mis, lub plawv, cov qog ntshav, cov qe ntshav, thiab cov qe ntshav, yog li qhia tias muaj hnub nyoog sib txawv hauv 3' rau 5' mature miRNA qhia piv yuav yog cov ntaub so ntswg-dependent [42]

Nyob rau hauv lub hnub nyoog ntawm tiam tom ntej sequencing, nws tau pom tias ib tug ib leeg miRNA locus muaj peev xwm tsim tau ob peb txawv miRNA isoforms los yog isomiRs, uas yog miRNA sequence variants uas tau hloov 3' thiab/los yog 5' kawg vim nucleotide. ntxiv, tshem tawm, lossis hloov pauv [43]. Lub biogenesis ntawm isomiRs tuaj yeem yog template-dependent, ua rau 5' lossis 3' nucleotide hloov pauv, lossis tsis yog tus qauv, ua rau tom qab hloov pauv RNA kho thiab tailing [44]. IsomiRs tuaj yeem faib ua 3', 5', polymorphic, thiab sib xyaw, nyob ntawm qhov sib txawv ntawm qhov sib txawv thiab kev hloov pauv hauv qhov ntev [4]. Kev hloov pauv tom qab kev loj hlob xws li trimming (tshem tawm ntawm nucleotides ntawm exoribonucleases ntawm 3' kawg) thiab tailing (ntxiv cov nucleotides los ntawm terminal nucleotidyl transferases ntawm 3' kawg) ua rau 3' isomiRs (tseem hu ua 3'-isomiRs. -trimmed thiab 3'-isomiR-tailed)[43-45]Nws kuj tau tshaj tawm tias 5' isomiRs feem ntau tsim los ntawm qhov tsis tseeb cleavage ntawm miRNA sequences ntawm Drosha thiab/los yog Dicer[43]. Polymorphic isomiRs muaj cov kev hloov pauv hauv cov kab ke paub tab thiab tsis hloov qhov ntev, thaum sib xyaw isomiRs muaj kev hloov pauv hauv qhov ntev thiab ntu [46,47]. Qhov tseem ceeb, tiam ntawm isomiRs tau pom tias yog cell- thiab cov ntaub so ntswg tshwj xeeb hauv cov tsiaj, thiab lawv tau siv los ua biomarkers ntawm mob qog noj ntshav thiab cuam tshuam rau Alzheimer's disease [48,49].

Muaj qee qhov kev tshawb fawb uas qhia meej txog lub luag haujlwm ntawm isomiRs hauv cov ntsiab lus ntawm kev laus. Tsis ntev los no, isomiR-19a-3p tau pom tias muaj kev nce ntxiv hauv cov neeg tsis noj qab haus huv centenarians thaum piv nrog cov neeg noj qab haus huv centenarians, qhia tias isomiR no tuaj yeem siv los ua tus cim rau kev laus noj qab haus huv [28]. Tsis tas li ntawd, isomiR sequencing ntawm metformin-kho (lifespan-extension kev kho mob) tib neeg umbilical-vein endothelial hlwb (HUVECs) thaum lub sij hawm replicaative senescence qhia tau hais tias non-canonical sequences accounted rau yuav luag 40 feem pua ​​ntawm tag nrho cov miRNA pas dej ua ke, qhov twg kev kho mob metformin kuj tau hloov pauv cov txiaj ntsig zoo. Kev nplua nuj ntawm 133 isomiRs uas tau txheeb pom tias yog qhov txawv ntawm 73 tus neeg miRNAs [50]. Interestingly, lub hom phiaj cov noob ntawm cov miRNAs thiab isomiRs tau pom tias yog ib feem ntawm phosphatidylinositol-3-kinase (PI3K)-Akt txoj kev thiab lub hom phiaj mammalian ntawm rapamycin (mTOR) qhia txoj hauv kev [50]. Qhov tseem ceeb, feem ntau isomiRs cuam tshuam los ntawm kev kho mob metformin tau txheeb xyuas tias yog 3'isomiRs; Txawm li cas los xij, nyob ib ncig ntawm 5 feem pua ​​​​tau raug txheeb xyuas tias yog 5' isomiRs, uas tau pom tias hloov cov noob sib lawv liag thiab tau txais ntau dua ntawm cov hom phiaj hom phiaj uas tsis muaj nyob hauv miRNA lub hom phiaj hauv txoj kev tshawb no [50]. Ib zaug ntxiv, isomiRs zoo li yog cov cim zoo rau kev ntsuas kev noj qab haus huv kev laus thiab kev ua neej ntev. Txawm li cas los xij, kev cuam tshuam txog kev lom neeg ntawm kev hloov pauv hauv isomiRs los ntawm kev laus thiab kev laus yuav tsum tau tshawb nrhiav ntxiv.

Cov kev tshawb fawb tau tshaj tawm tias tsawg kawg yog rau lub hauv paus-pair match ntawm miRNA rau mRNA yog qhov tsim nyog rau kev qhia txog cov noob caj noob ces, thiab vim tias qhov kev sib txuas ntxiv no nrog rau lub hom phiaj mRNA, ib tus neeg miRNAs tuaj yeem muaj ntau lub hom phiaj mRNAs (kwv yees li 100 mRNAs) thiab tuaj yeem ua rau tib lub sijhawm. lub hom phiaj sib txawv 3-UTR qhov chaw ntawm tib mRNA, thaum sib txawv miRNAs kuj tuaj yeem tsom rau tib mRNA, uas txhawb nqa qhov nyuaj ntawm cov kev tswj hwm cov txiaj ntsig rau tib mRNA [32]. Qhov no qhia tau hais tias txhua hom cell thiab cov ntaub so ntswg nthuav tawm cov qauv nyuaj heev ntawm miRNAs, thiab kev tsis sib haum xeeb ntawm ib lossis ntau yam hauv cov tes hauj lwm miRNA tuaj yeem ua rau homeostasis imbalance, shortened lifespan, thiab kab mob [5152]. Qhov tseeb, centenarians qhia upregulation ntawm kev qhia ntawm miRNAs, uas yog miR-16, miR-18a, thiab miR-21, thaum mRNA qhia ntawm RNA Polymerase Ⅱ, Drosha, Exportin{{ 10}}, thiab Dicer kuj yog tag nrho cov upregulated piv nrog octogenarians [29].

3. Lub Hom Phiaj-Directed miRNA Degradation thiab nws lub luag haujlwm hauv cov txheej txheem Cellular tseem ceeb

Nyob rau hauv sib piv rau miRNA biogenesis, lub luag hauj lwm ntawm miRNA decay / degradation - tshwj xeeb tshaj yog ntawm lub hom phiaj-directed miRNA degradation (TDMD) - nyob rau hauv kev noj qab haus huv thiab kab mob tsuas yog pib elucidated. TDMD tshwm sim thaum lub hom phiaj RNA tuaj yeem ua rau muaj kev puas tsuaj / lwj ntawm nws cov cognate miRNA es tsis txhob siv lub hom phiaj kev tsim txom, uas tso cai rau kev hloov pauv ntawm ntau yam txheej txheem ntawm tes. TDMD tshwm sim thaum muaj kev sib txuas txuas ntxiv ntawm 3' cheeb tsam ntawm miRNA, uas ua rau muaj kev hloov pauv uas txhawb nqa 3' kawg kom tso tawm los ntawm lub hnab ntawv khi ntawm Ago PAZ domain [53-55] Tom qab raug ntawm 3'end tso cai rau enzymatic degradation ntawm miRNA [54] cov txheej txheem no kuj tseem tuaj yeem nrog kev hloov kho tom qab hloov pauv ntawm miRNA ib ntus, xws li tailing (los ntawm qhov chaw nres nkoj nucleotidyl transferases) thiab trimming (los ntawm 3'-rau{{9 }}'exonucleases), ua rau tsim cov isomiRs[56,57]. TDMD cov hom phiaj tseem tuaj yeem ntes Ago2 hauv ib qho kev sib haum xeeb uas tso cai rau kev nthuav tawm ntawm miRNA 3' kawg rau tailing thiab trimming thaum txuas ntxiv mus rau Ago2 [54,55]. Interestingly, nws muaj peev xwm los ntsuas miRNA decay tus nqi nyob rau hauv mammalian hlwb los ntawm kev sib xyaw ua ke xws li metabolic RNA 4sU-raws li "pulse-chase" labeling nrog high-throughput RNA sequencing, nyob rau hauv trimming thiab tailing tau pom tias yuav dynamic lub sij hawm nyob rau hauv fibroblasts [ 57] Cov txheej txheem no tuaj yeem ua pov thawj tias muaj txiaj ntsig zoo hauv kev tshawb fawb yav tom ntej ntsuas miRNA lwj thoob plaws lub cev laus.

Ib tug puv tes ntawm cov kev tshawb fawb tau tshawb nrhiav endogenous TDMD thiab nws txoj haujlwm hauv cov tsiaj nyeg, txheeb xyuas cov hom phiaj tseem ceeb hauv cov xwm txheej no. Piv txwv li, Serpinel, uas encodes serine-threonine protease inhibitor, ua lub hom phiaj TDMD los tswj miR-30b-5p thiab miR-30c-5p degradation hauv nas. fibroblasts, yog li txhawb lub cell-cycle rov nkag ntawm quiescent fibroblasts [58]. Interestingly, tag nrho miR-30 tsev neeg (miR-30a -30b,-30c,-30d, thiab-30e) muaj peev xwm cuam ​​tshuam nrog Serpinel; Txawm li cas los xij, tsuas yog miR-30b thiab miR-30c nthuav tawm qhov txuas ntxiv 3' kawg complementarity (tseem hu ua 3C pairing) rau Serpinel cov ntawv sau tseg, ua pov thawj tias qhov kev sib tw 3C no yog qhov tseem ceeb rau TDMD [58]. Ua ke, Serpinel.miR-30b/c kev sib cuam tshuam ua lub luag haujlwm tseem ceeb hauv cov tsiaj txhu ntawm tes phenotypes los ntawm kev ua kom yooj yim rau lub voj voog rov nkag ntawm cov hlwb quiescent. Lwm qhov piv txwv ntawm ib lub hom phiaj endogenous TDMD, cov neuronal regeneration-related protein (Nrep) gene, tau tshaj tawm rau ncaj qha miR-29b degradation los ntawm 3' trimming, tswj tag nrho lub cev muaj zog sib koom tes thiab kev kawm tsav hauv nas[59]. Nquag, Nrep txwv miR-29b qhia ib leeg rau cerebellar Purkinje neurons, thaum cuam tshuam ntawm miR-29 qhov chaw hauv Prep nthuav dav miR-29b qhia rau cerebellar granular txheej, ua rau txawv txav. Kev kawm tsav tsheb thiab kev sib koom tes hauv nas [59]. Tshwj xeeb tshaj yog, kev sib tsoo ntawm miR-29 qhov chaw hauv Nrep hauv neural progenitor cells ua rau tsis muaj miR-29 isoforms uas tsim los ntawm 3' trimming lossis tailing[59]. Qhov zoo siab, qhov chaw Prep miR-29 kuj tau pom tias muaj qhov sib luag zoo sib xws nrog cov tsis-coding RNA libra hauv zebrafish, uas tswj kev ntxhov siab zoo li thiab tshawb nrhiav tus cwj pwm hauv zebrafish [59]. Sib koom ua ke, TDMD, los ntawm cov hom phiaj endogenous, yog qhov tseem ceeb hauv kev tswj hwm lub paj hlwb kom zoo thiab kev coj cwj pwm thiab tswj cov phenotypes ntawm tes.

4. Kev nthuav qhia Profiles ntawm miRNA yog Dynamic thiab yog cov ntaub so ntswg tshwj xeeb thoob plaws hnub nyoog

Thaum lub sij hawm cov ntaub so ntswg laus, muaj ib tug zuj zus poob nyob rau hauv miRNA abundance, uas yog thawj zaug qhia vim lub hnub nyoog-sociated txo nyob rau hauv miRNA biogenesis uas tshwm sim los ntawm downregulation ntawm Dicer [60]. Tseeb tiag, miRNA biogenesis tau pom tias txhim kho kev ntxhov siab thiab kev ua neej ntev hauv C. elegans thiab hauv cov ntaub so ntswg adipose hauv cov nas, thaum cov miRNAs tshwj xeeb tau cuam tshuam nrog kev ntxhov siab thiab kev laus [23,60]. Tsis ntev los no, nws tau pom tias miRNA-biogenesis noob. yog, qhov tseeb, tau tsom ntau heev los ntawm miRNAs uas koom nrog cov txheej txheem muaj hnub nyoog, xws li miRNA-71, uas tau pom tias txo qis kev qhia thoob ntiaj teb miRNA thiab ua rau muaj kev nce ntxiv ntawm mRNA kev hloov pauv nrog hnub nyoog [19]. Cov txiaj ntsig no tau ua raws li cov pov thawj yav dhau los uas tau tsim miR-71 ua ib qho ntawm cov miRNA uas tau kawm tshaj plaws nyob rau hauv cov ntsiab lus ntawm kev laus thiab kev ua neej ntev, nrog rau nws cov lus qhia tau raug kho kom zoo thoob plaws hauv cov neeg laus thaum ntxov mus rau nruab nrab [24,25]. Interestingly, miR-71 kuj tsis ntev los no tau tshaj tawm los txhawb ubiquitin-dependent protein hloov pauv, tshwj xeeb hauv cov hnyuv, ua kom ntev lub neej ntawm C. elegans, thaum nws inhibition cuam tshuam cov kab mob proteostasis [61]. Tshwj xeeb, cov khoom noj tsis hnov ​​​​tsw hnov ​​​​los ntawm C. elegans ntawm ciliated AWC olfactory neurons 1) txhawb lub cell-nonautonomous kev tswj ntawm ubiquitin-dependent protein degradation los ntawm ubiquitin-proteasome system (UPS) thiab ntawm endoplasmic-reticulum (ER)-kawm protein degradation. (ERAD) thiab 2) augment heat stress resistance nyob rau hauv txoj hnyuv [61]. Cov kws sau ntawv tau pom tias miR-71 tshwj xeeb inhibits Tus Xov Tooj-receptor-domain protein (TIR-1) hauv amphid tis "C"(AWC) olfactory neurons, thaum miR-71 thiab/los yog TIR{ {29}}Knockout worms tso saib UPS thiab ERAD tsis ua haujlwm, tshem tawm qhov cuam tshuam ntawm cov khoom noj hauv cov lus teb no [61]. Ib lub ntsiab lus tseem ceeb uas tshwm sim yog tias miRNA cov kev tswj hwm kev sib txuas lus muaj kev sib txuam ntau hauv ntau lub cev qauv, thiab miRNA qhia cov ntaub ntawv zoo li yog ob qho tib si cov ntaub so ntswg thiab, tib lub sijhawm, cuam tshuam nrog ntau cov ntaub so ntswg.

Feem ntau cov kev tshawb fawb uas tau tshawb fawb txog lub luag haujlwm ntawm miRNAs hauv cov ntaub so ntswg laus ib txwm tau tsom mus rau kev sim siv cov qauv feem ntau los ntawm lub hlwb thiab cov leeg nqaij pob txha, tej zaum vim cov ntaub so ntswg 'propensity rau kev loj hlob ntawm cov kab mob muaj hnub nyoog [62] Ib qho kev kawm heev. miRNA hauv kev laus thiab cov kab mob muaj hnub nyoog yog miR-34. Qhov miRNA no tau pom tias muaj kev hloov pauv hauv kev laus C. elegans [63], thaum nws qhov kev nthuav dav dhau mus txuas ntxiv txoj sia nyob hauv Drosophila thiab txo qhov kev xav rau hnub nyoog ntsig txog neurodegeneration [64]Txawm li cas los xij, cuam tshuam rau lwm yam kab mob, cov tswv cuab ntawm miR{{7} } tsev neeg ua lub luag haujlwm tsis zoo hauv kev laus ntawm cov tsiaj hauv lub hlwb, qhov chaw kho mob ntawm miR-34c tau pom nyob rau hauv nas hippocampus nyob rau hauv ob qho tib si laus laus thiab AD qauv thiab yog txuam nrog kev txawj ntse poob [65]. Tsis tas li ntawd, muaj hnub nyoog txuam nrog kev tswj hwm ntawm miR-29a thiab miR-29b hauv nas hlwb ua rau muaj kev tsis haum xeeb ntawm microglia thiab nce hauv neuroinflamation, kuj yog ib qho cim ntawm lub hlwb laus [66]. Ib yam li ntawd, thaum lub sij hawm kev laus, cov leeg nqaij degeneration thiab rov tsim dua tshiab yog qhov tsis txaus, ua rau poob hauv cov leeg nqaij homeostasis. Tsis tas li ntawd, miRNAs, uas yog miR-29, tau txuas rau sarcopenia, muaj hnub nyoog cuam tshuam txog kev ua haujlwm ntawm cov leeg nqaij, thiab tau pom tias yuav hloov kho apoptosis, senescence, thiab insulin-zoo li kev loj hlob zoo (IGF-1) qhia. hauv cov leeg nqaij laus [67] Yog li, miRNAs tuaj yeem siv los ua biomarkers ntawm kev laus hauv ntau tshaj ib cov ntaub so ntswg thiab rau cov hnub nyoog tshwj xeeb uas muaj feem xyuam nrog cov phenotypes xws li sarcopenia.

Tsis ntev los no, ib pab pawg ntawm kev tshawb fawb tshawb nrhiav lub luag haujlwm ntawm miR-206 thaum lub sij hawm vascular (xws li cov leeg plawv) thiab cov leeg pob txha laus thiab homeostasis[68-74]. Augmented qhia ntawm miR-206 tau txuas rau vascular laus, tshwj xeeb tshaj yog nyob rau hauv cov neeg uas muaj arrhythmias, [74] thiab kuj tau pom tias inhibit qhov loj hlob ntawm vascular du leeg hlwb thiab txhawb atherosclerosis [72,73]. Cov kev tshawb fawb no hais txog qhov tseem ceeb ntawm kev tshawb nrhiav miRNA kev tswj hwm hauv ib cov ntaub so ntswg tshwj xeeb kom muaj peev xwm nrhiav tau cov hom phiaj kho mob tshiab rau cov kab mob tshwj xeeb, hnub nyoog ntsig txog.

Ua raws li tag nrho cov kev tshawb pom tsis ntev los no rau hauv kev txiav txim siab, nws pom tseeb tias miRNA cov kev tswj hwm kev sib koom ua ke daws kev laus thiab kev ua neej ntev rau qee qhov. Txawm li cas los xij, nws yog ib qho tseem ceeb los qhia meej txog lub luag haujlwm ntawm miRNAs rau txhua tus qauv kab mob vim yog qhov nyuaj ntawm miRNA kev tswj xyuas cov tes hauj lwm thiab ntau lub hom phiaj muaj peev xwm uas txhua tus miRNA yuav muaj. Hauv cov ntu nram qab no, peb qhia txog qhov cuam tshuam ntau dua ntawm miRNAs 'tshwj xeeb tshaj yog muaj hnub nyoog txog kev txo qis proteostasis uas cuam tshuam nrog cov protein degradation thiab tshem tawm cov txheej txheem, suav nrog hauv daim duab 1, thiab nkag mus rau hauv lawv qhov muaj peev xwm cuam tshuam rau kev sib sau ntawm cov protein ntau thaum lub sij hawm mammalian laus.

5. Lub luag hauj lwm ntawm miRNA Regulation nyob rau hnub nyoog-Related Autophagic poob nyob rau hauv lub hlwb thiab pob txha pob txha

Piav raws li cov kev hloov pauv loj ntawm ntau txoj hauv kev cuam tshuam txog kev degradation thaum lub sij hawm mammalian cov ntaub so ntswg laus, cov ntaub ntawv tshawb fawb tau tsom mus rau miRNA cov kev tswj hwm kev koom tes nrog rau txoj kev autophagy-lysosome (ALP), nrog rau qhov tshwj xeeb tseem ceeb ntawm lub hom phiaj mammalian ntawm rapamycin (mTOR) complex, feem ntau. nyob rau hauv lub hlwb thiab cov leeg [24,75].Inukai thiab cov npoj yaig (2012) tau ua ib qho ntawm thawj cov kev tshawb fawb siv Solexa sib sib zog nqus sib sib zog nqus los txheeb xyuas qhov sib txuas ntawm qhov sib txawv ntawm miRNAs thaum lub sij hawm lub hlwb laus thiab mTOR signaling [24].cistanche แอมเวHauv txoj kev tshawb no, feem ntau ntawm qhov sib txawv ntawm miRNAs tau poob qis hauv cov txheeb ze muaj ntau nyob rau hauv 24-25-cov nas hnub nyoog hli piv nrog 5-hli, nrog KEGGenrichment tsom xam qhia tias miRNAs, uas yog miR-5620 isomiR thiab miR-341 isomiR, koom nrog hauv mTOR/ protein kinase B(Akt)/Forkhead box class O (FOXO) signaling [24].

Ib hom autophagy, hu ua macrophagy, suav nrog kev degradation thiab recycling ntawm cytoplasmic Cheebtsam, nrog rau cov khib nyiab ntawm tes thiab misfolded proteins, uas tau ntim rau hauv ob-membrane vesicles hu ua autophagosomes, uas yog fused nrog lyso-somes kom degraded los ntawm lysosomal hydrolases. 75] ib. Protein aggregates tuaj yeem engulfed los ntawm autophagosomes thiab degraded, thiab kev laus yuav hloov autophagic clearance los ntawm de-fects nyob rau hauv autophagosome tsim, ua tsis tau tejyam autophagosome-lysosome fusion, thiab lysosome acidification [76]. Lub hnub nyoog ntsig txog autophagic dysfunction kuj tseem tuaj yeem ua rau kev loj hlob ntawm cov kab mob uas muaj hnub nyoog, xws li sarcopenia thiab cov kab mob neurodegenerative. Yog xav paub ntxiv, saib [75]. Thaum lub sij hawm skeletal leeg laus, autophagic kev ua ub no tau pom tias yuav txo qis hauv cov neeg laus uas muaj sarcopenia thiab hauv murine leeg nqaij, qhov twg cov protein ntau ntawm LC3, ib qho cim ntawm autophagosomes thiab autolysosomes, thiab E1-zoo li enzyme ATG7 poob nrog lub hnub nyoog [ 62] ib. Nws tsis ntev los no tau lees paub tias miR-34a yog ib qho tseem ceeb hauv kev ua haujlwm autophagic hauv lub hlwb laus, nrog rau nws qhov kev txhim kho uas ua rau muaj qhov tsis zoo autophagy thiab mitochondrial dynamics hauv d-galactose-induced nas qauv ntawm kev laus [77]. Hauv tib txoj kev tshawb fawb no, autophagic dysfunction tau thim rov qab los ntawm kev tswj hwm ntawm miR-34ib qho inhibitor rau d-galactose-induced SH-SY5Y hlwb thiab ua rau muaj kev hloov pauv ntawm cov kab mob autophagy ntsig txog cov protein, xws li LC3, Beclin 1, ATG7, thiab qhov degradation ntawm P62[7]Ua ua ke, miRNA-34a tej zaum yuav yog lub hom phiaj kho mob zoo rau kev txo qis thiab/los yog thim rov qab lub hnub nyoog ntsig txog autophagic poob rau hauv cov tsiaj hauv lub hlwb.

Muscle-enriched miRNAs, hu ua myo-miRNAs, xws li miR-1 thiab miR-206, tuaj yeem tswj cov hom phiaj los ntawm PI3K/AKT/mTOR/FOXO txoj hauv kev, uas tswj cov cell-cycle, proliferation, thiab Cov txheej txheem sib txawv hauv myocytes [68-71]. Tsis ntev los no, cov neeg mob hemodialysis tau txais kev cob qhia lub cev tsis tu ncua tau pom tias muaj qis dua ntawm miR-206, uas ua rau muaj ntau dua myogenesis thiab tsawg dua plawv calcifications, ib qho cim ntawm vascular laus [69]. Cov kws sau ntawv xaus lus tias, tom qab kev cob qhia tsis tu ncua, kev txo qis ntawm miR-206 tuaj yeem txhawb nqa myogenesis los ntawm insulin-zoo li kev loj hlob 1 (IGF1) khi thiab ua kom txoj hauv kev PI3K / AKT / mTOR [70]. Ib yam li ntawd, hauv tib neeg cov pob txha pob txha, 26 miRNAs raug txheeb xyuas los ntawm lub hnub nyoog, kev tawm dag zog, lossis kev sib xyaw ntawm ob qho tib si, uas yog cuaj ntawm miRNAs, uas yog miR-99a-5p, miR{{18 }}b-5p, miR-100-5p, miR-199a, thiab miR-196b-5p, tau lees paub cov hom phiaj ua ntu zus hauv 3'UTRs ntawm lub hom phiaj genes koom nrog hauv Akt/mTOR-kev taw qhia txoj hauv kev, xws li mTOR, Akt, kev tswj hwm cov protein ntawm MTOR complex 1 (RPTOR), thiab IGF1 [71].

Qhov tseem ceeb, miR-378 kuj tau txheeb xyuas tias yog qhov tseem ceeb rau cov leeg nqaij homeostasis los ntawm kev txhawb nqa-ing autophagy los ntawm kev tsom ncaj qha ntawm phosphoinositide-dependent protein kinase 1 (PDK1), txhawb nqa Akt-mTORCl signaling, thiab txo cov myocyte apoptosis ntawm caspase 9 lub hom phiaj. [69]. MiR-378-knockout nas tau nthuav tawm qhov tsis zoo autophagy thiab cov khoom ntawm cov mitochondria tsis raug, thaum miR-378 overexpression tau pom tias txo phosphorylation ntawm unc-51-zoo li autophagy activating kinase 1 (ULK1), tom qab txhawb tsim ntawm autophagosomes, ib qho txiaj ntsig uas tau lees paub los ntawm upregulated LC3 qhia thiab puncta hauv C2C12myotube cell kab [69]. Txoj kev tshawb no tseem ceeb heev vim nws lees paub tias miR-378 ua haujlwm tau zoo hauv kev txhawb nqa autophagy thiab txheeb xyuas nws ob lub hom phiaj ncaj qha: (1) PDK1, uas ua rau Akt thiab mTORCl los txhawb autophagy hauv cov leeg pob txha thiab (2) Caspase9, uas suppresses myocyte apoptosis. Txawm li cas los xij, tseem muaj ntau yam ntawm miRNA kev tswj hwm ntawm autophagy yuav tsum tau tshawb nrhiav hauv cov ntsiab lus ntawm cov ntaub so ntswg laus, tshwj xeeb tshaj yog nyob rau hauv hom tsiaj.

Nyob rau hauv cov ntsiab lus ntawm cov hnub nyoog muaj feem xyuam nrog cov protein sib sau ua ke, miR-1 tau pom los tswj cov leeg nqaij thiab txhim kho pharyngeal siv los teb rau cov kev ntxhov siab proteotoxic thaum lub sij hawm, thaum tseem suppressing polyglutamine 35 (polyQ35) protein aggregation hauv C.elegans [30 ]. Ib v-ATPase subunit, vha-13 tau txheeb xyuas tias yog lub hom phiaj ncaj qha ntawm miR-1, uas tswj hwm lysosomal biogenesis thiab ua haujlwm [30]. Yog li, miR-1 yuav tsum tau kawm raws li lub tswv yim kho mob rau kev tawm tsam cov leeg nqaij tshwj xeeb sib sau ua ke thiab txhim kho cov nqaij ntshiv thoob plaws lub neej. Yav dhau los, nce qib ntawm miR-1 tau pom los txhawb autophagy yog li txo cov tsub zuj zuj ntawm cov protein aggregates hauv C. elegans thiab mammalian hlwb[78]Qhov tseem ceeb, hauv nas cortical neurons thiab HeLa hlwb, miR-1 activates autophagy los ntawm lub hom phiaj ntawm Tre-2/Bub2/CDC16(TBC) Rab GTPase-activating protein (TBC1D15) nyob rau hauv teb rau cov tsub zuj zuj ntawm mutant yos hav zoov aggregates[78]. TBC1D15 tau pom tias thaiv autophagy los ntawm inactivating Rab7, uas tswj autophagosome thiab lysosome fusion. Ib zaug ntxiv, miR-1 zoo nkaus li yog ib tus neeg sib tw ua haujlwm zoo rau kev tiv thaiv kev laus uas tsom rau cov txheej txheem autophagy.

6.miRNAs Mediate Ubiquitin-Proteosome System hauv Brain Aging thiab Muscle Atrophy

Lub ubiquitin-proteasome system (UPS) yog cov txheej txheem ntawm cellular proteolytic degradation uas muaj 26S proteasome ua nws lub hauv paus tivthaiv, suav nrog ob 19S regu-latory Cheebtsam thiab ib qho 20S core [79]. Kev ua haujlwm Proteasomal txo qis thaum lub sijhawm laus ib txwm muaj thiab hauv neurodegeneration [80]. Hauv xyoo tas los no, ob txoj kev tshawb fawb tau piav qhia txog kev koom tes ntawm miRNA kev tswj hwm ntawm UPS-txog kev hloov pauv thoob plaws hauv kev laus hauv cov ntsiab lus tsis muaj kab mob [81-83]. Piv txwv li, miR-127-5p tau pom tias muaj kev txo qis hauv lub hlwb ntawm cov hnub nyoog C57BL/6] cov nas uas muaj LPS-induced ischemia, thiab thawj zaug, tau txheeb xyuas 26S proteasome non-ATPase regulatory subunit 3 (Psmd3) raws li ib qho ntawm nws lub hom phiaj [82]. Txoj kev tshawb no tseem ceeb vim tias cov kws sau ntawv tsis yog tsuas yog muab lub hlwb miRNome los ntawm kev paub tab miRNA sequencing tab sis kuj tau txheeb xyuas qhov tshiab miRNA hauv lub hlwb, miR-127, uas cuam tshuam nrog cell apoptosis thiab proteasomal kev ua haujlwm thaum laus thiab ischemia. Tsis tas li ntawd, hauv cov neeg nqa khoom noj qab haus huv ntawm apolipoprotein E (ApoE c4) poly-morphism, txuas rau Kev tshem tawm thiab ua kom muaj kev pheej hmoo siab rau AD txoj kev loj hlob, miR-153-3p tau pom tias yuav nce ntxiv, ua rau muaj kev cuam tshuam ntawm nuclear erythroid{{ 23}}related-factor-2(Nrf2)-mediated proteasomal function thiab erythrocyte A tsub zuj zuj hauv plasma [81] Tsis tas li ntawd, cov khoom muaj feem cuam tshuam nrog proteasome, xws li plasma Kelch-like ECH-associated protein 1 (Keapl) thiab erythrocyte histone deacetylase 6 (HDAC6), kuj tau nce ntxiv hauv Apoes4 cov neeg nqa khoom hauv kev sib piv nrog cov neeg tsis muaj peev xwm [81]. ApoE a4 polymorphism, nrog rau cov khoom sib txuas nrog cov proteoasome thiab miR-153-3p, tuaj yeem siv los ua cov ntshav los yog cov cim circulating rau kev ntsuas qhov tsis zoo rau A tsub zuj zuj thiab cuam tshuam nrog kev ua haujlwm tsis zoo ntawm lub hlwb thaum lub hlwb laus, thiab, tib lub sijhawm, rau kev ntsuam xyuas lub propensity rau txoj kev loj hlob ntawm pathological hnub nyoog hais txog neurodegeneration thiab protein aggregation, yog li muab ib tug tsis-invasive ntsuas rau cov neeg nqa khoom.

Cov leeg nqaij atrophy yog tus cwj pwm los ntawm qhov tsis zoo ntawm cov protein degradation los ntawm UPS txoj kev [83].npaum li cas cistanche cojHauv cov leeg pob txha, cov leeg ntiv tes ntiv tes 1 (MuRF1) thiab cov leeg nqaij atrophy F-box (MAFbx)/atrogin-1 yog E3 ubiquitin ligases uas tau xav tias yuav koom nrog hauv ubiquitination ntawm substrates rau degradation los ntawm 26S proteasome, qhov twg. nce hauv cov khoom UPS no txhawb cov leeg nqaij atrophy [83]. Thaum lub sij hawm cov leeg nqaij atrophy, muaj overexpression ntawm MuRFI thiab MAFbx / atrogin -1, thaum inhibition ntawm cov khoom no slows cov leeg nqaij [84,85].bioflavonoidsNtau qhov kev tshawb fawb tau qhia txog lub luag haujlwm ntawm miRNAs hauv kev tswj hwm ntawm MuRFl thiab MAFbx/atrogin-1 qhia. Piv txwv li, miR-23a tau pom tias inhibit qhov kev txhais lus ntawm MuRFl thiab MAFbx/atrogin-1, tiv thaiv cov leeg nqaij atrophy hauv dexamethasone-induced leeg nqaij atrophy nas qauv [86].dab tsi yog cistancheTsis tas li ntawd, nce kev qhia ntawm cov leeg nqaij tshwj xeeb miR-1 tau pom los txo HSP70levels, txo AKT phosphorylation thiab ua rau ua kom FOXO3 thiab thaum kawg ua rau kev tswj hwm ntawm MuRFl thiab MAFbx/atrogin-1 qhia thaum lub sij hawm dexamethasone-induced nqaij atrophy hauv nas [87]. Tshwj xeeb, raws li dexamethasone induction, miR-1, tswj cov dephosphorylation thiab tom qab ua kom FoxO3a los ntawm HSP70/Akt signaling, uas ncaj qha los yog tsis ncaj qha inhibits proteins uas tawm tsam cov leeg nqaij atrophy [87] Tsis ntev los no, inhibition ntawm MuRF1 thiab MAFbx / atrogin-1 kev sau ntawv tau pom tias txhim kho cov leeg tsis zoo hauv cov leeg pob txha (tshwj xeeb, cov leeg nqaij gastrocnemius) ntawm 40-wk-laus senescence-accelerated nas prone 8 (SAMP8) nas thaum piv nrog cov hnub nyoog sib txuam nrog senescence -accelerated nas resistant (SAMR1) nas tom qab stimulation nrog epigallocatechin-3-gallate (EGCG), catechin tivthaiv nyob rau hauv ntsuab tshuaj yej paub ameliorate nqaij poob [88]. EGCG tau pom tias inhibit myostatin thiab upregulate miR-486-5p, uas ncaj qha suppresses phosphatase thiab tensin homolog (PTEN), augmenting Akt phosphorylation thiab ua rau inhibition ntawm active FoxOla thiab inhibition ntawm MuRFl thiab MAFbx / atrogin{{ 25}} transcription nyob rau hauv lub cev nqaij daim tawv ntawm 40-wk-laus SAMP8 nas raws li nyob rau hauv lig passage C2C12 myoblast hlwb [88]. Txoj kev tshawb no tau nthuav tawm qhov tshwj xeeb ntawm cov leeg-tsis cuam tshuam siv EGCC tivthaiv ntawm cov tshuaj yej ntsuab los hloov cov kev cai miRNA hauv cov txheej txheem ubiquitin-proteasome thiab PI3K / Akt / FOXO signaling hauv cov leeg pob txha. Qhov tseeb, cov kev tshawb pom no muab pov thawj tias miRNA koom nrog UPS ua kom txhawb nqa cov leeg nqaij atrophy feem ntau los ntawm kev tsom mus rau MuRFI thiab MAFbx/atrogin-1 hauv cov leeg pob txha.

7.miRNAs li UPR thiab Protein-Aggregation Regulators

Nyob rau hauv cov xwm txheej kev ntxhov siab, misfolded proteins nyob rau hauv ER lumen thiab elicit UPRER rau degradation ntawm cov proteins ntawm peb txoj kev tseem ceeb, uas yog cov protein kinase RNA-zoo li ER kinase (PERK), inositol-yuav tsum tau enzyme -1 alpha (IRE-1o)/X-box binding protein-1 (XBP-1), thiab activating transcription factor 6(ATF6) pathways[890]. UPRFR kev ua haujlwm tau txo qis thaum muaj hnub nyoog ER kev ntxhov siab, thaum overexpression ntawm XBP-1 tuaj yeem txhim kho ER kev ntxhov siab thiab kev ua neej ntev [89,90]. Zuag qhia tag nrho, nws pom tseeb tias UPRER ua lub luag haujlwm tseem ceeb hauv kev laus thiab kev ua neej.

miRNAs tau tshaj tawm los ncaj qha hloov kho ER kev ntxhov siab lossis, piv txwv li, tau txais kev tswj hwm ntawm ER kev ntxhov siab [91]. Qhov tseeb, ER kev ntxhov siab sensors, uas yog PERK, tuaj yeem ncaj qha tswj hwm miRNA qhia kev sib koom tes pro- thiab anti-apoptotic signaling raws li ER kev nyuaj siab [92]. Piv txwv li, miR-30c-2-3p ntawm PERK-mediated signaling ua rau txo qis hauv XBP-1 mRNA, uas tom qab txhawb kev tuag ntawm tes hauv NIH-3T3 fibroblasts [92 ]Lub sijhawm ER kev ntxhov siab, kev txo qis ntawm miR-106b-25 tsev neeg ntawm PERK ua kom tso cai rau kev ua kom cov pro-apoptotic B-cell lymphoma 2 (BCL-2) tsev neeg cov noob xws li Bim, yog li eliciting ER-kev nyuaj siab-induced apoptosis hauv cell kab [93]. Kev txo qis ntawm miR106b-25 tsev neeg thiab ER-kev nyuaj siab-induced apoptosis kuj pom nyob rau hauv ALS tus qauv (mutant SOD1 G93A), uas txuas cov miRNA tsev neeg thiab nws lub hom phiaj rau neurodegeneration hauv ALS[93]. Tsis ntev los no, nyob rau hauv lub cortical thiab hippocampal neurons ntawm nas, raws li stimulation nrog advanced glycation ntawm cov khoom kawg ntawm bovine serum albumin (AGE-BSA) induce ER stress, miR-24,-27b,{{ 30}},-224,-290,-351, thiab-488 tau pom tias raug txo qis, thaum mRNA ntawm UPR cov hom phiaj (Prk, Irela, Chop, thiab Puma) tau upregulated, yog li qhia tau hais tias cov miRNAs yog tej zaum UPR regulators [94]Siv miRNA-target-prediction algorithms, cov sau phau ntawv pom tias PERK yog tsom los ntawm miR-24 thiab miR-488, Irelo los ntawm miR{{ 40}},-124,-290,-351, thiab -488, Chop los ntawm miR-224, thiab Puma los ntawm miR-24,{{ 47}}b, thiab -351 [94]. Thaum raug cov suab thaj, cov qib siab glycation ntawm cov protein ua rau muaj kev sib cuam tshuam ntawm cov khoom siv glycation kawg (AGEs) thiab RAGE (receptor of AGEs), uas txhawb nqa cov tsub zuj zuj ntawm aberrant toxic proteins, tom qab cellular oxidative stress, thiab ER stress [94]. Tsis tas li ntawd, qee qhov ntawm cov miRNAs no kuj tau pom nyob rau hauv kev qhia-profiling kev tshawb fawb hauv neurodegeneration, xws li miR-27b, -124, thiab -488 [95], qhia tias cov miRNAs tuaj yeem tsim nyog. cov cim ntawm kev laus hauv ob lub ntsiab lus. Txawm li cas los xij, kev sib raug zoo ncaj qha ntawm kev sib sau ua ke ntawm cov protein thiab miRNA dysregulation tseem yuav tsum tau tsim nyob rau hauv cov ntsiab lus ntawm ob qho tib si kev noj qab haus huv laus thiab hnub nyoog ntsig txog pathological neurodegeneration.

8. miRNA-Binding Proteins kuj tswj lub neej ntev los ntawm Proteostasis Network Cheebtsam

Ntau cov ntawv ceeb toom tau pom tias miRNA-binding proteins tswj ag-ing los ntawm proteostasis network Cheebtsam. Hauv C. elegans, piv txwv li, Argonaute, Dicer, Drosha, thiab DGCR8/Pasha tau pom tias tswj kev laus thiab kev ua neej ntev [19,24,25]. Argonaute-1 (alg-1) tau pom los txhawb kev ua neej nyob ntev, whereas Argonaute-2(alg-2) shortens lifespan qhov twg ntau ntawm cov noob sib txawv hauv mutant alg{{10 }} thiab alg{11}} C elegans yog ib feem ntawm insulin / IGF{12}} kev taw qhia (IS) txoj hauv kev, nrog kev tswj hwm ntawm DAF. 16/TXO [96]. Tsis tas li ntawd, tshwj xeeb hauv alg-1 mutants, qhov ntsuas kub ntawm qhov hluav taws xob 1 (hsf1), ib qho kev hloov pauv uas yog ib feem ntawm cov lus teb rau kev ntxhov siab thaum tshav kub kub, tau pom tias yuav tsum tau txo qis [96]. Huntingtin aggregation cell kab lis kev cai thiab cov qauv nas, nrog rau cov qauv kuaj tom qab los ntawm cov neeg mob Huntington tus kab mob, kuj tau qhia tias Argonaute-2(AGO2), ib qho tseem ceeb ntawm RISC, rov ua dua thiab sib sau ua ke hauv cov kev ntxhov siab granules nyob rau hauv striatal neurons uas qhia mutant Huntingtin (mHTT) aggregates, yog li cuam tshuam lig autophagosome thiab lysosome fusion thiab, nyob rau tib lub sij hawm, ua rau lub ntiaj teb no nce nyob rau hauv miRNA qhia [31].Txawm li cas los xij, vim qhov rov ua haujlwm ntawm AGO2. thiab kev tsim ntawm AGO2-miRNA complexes nyob rau hauv kev nyuaj siab granules, cov sau phau ntawv sau tseg tias tag nrho cov kev ua si miRNA, tshwj xeeb tshaj yog lub hom phiaj silence, yog hindered nyob rau hauv mHTT-expressing neurons [31]. Hauv qhov no, cov protein aggregates tau pom tias cuam tshuam nrog kev tshem tawm autophagic, uas txhawb nqa AGO2 tsub zuj zuj thiab kev hloov pauv hauv miRNA qib thiab kev ua haujlwm, tejzaum nws ua rau kev puas tsuaj rau neuronal. Cov txiaj ntsig no nthuav tawm qhov kev xav tshiab, suav nrog hauv daim duab 2, uas qhia txog lub luag haujlwm ntawm cov hnub nyoog ntsig txog protein sib sau ua ke hauv autophagic dysfunction, miRNA biogenesis, thiab miRNA kev ua haujlwm thaum lub sij hawm mammalian laus (Daim duab 2).

neuron ciaj sia taus los ntawm kev txo cov kev pheej hmoo tshwj xeeb rau thapsigargin-induced ER kev nyuaj siab, qhia tias miRNA biogenesis ntawm Dicer yog neuroprotective tiv thaiv ER kev nyuaj siab. Downreg-ulation ntawm Dicer thaum laus tuaj yeem cuam tshuam txog miRNA biogenesis thiab ua rau muaj kev ntxhov siab ER thiab cov neurodegeneration ntawm dopamine neurons[9]. Cov txheej txheem tsim kho tshiab xws li photoactivatable ribonucleoside-enhanced crosslinking thiab immunopre-cipitation (PAR-CLIP) sequencing tau txheeb xyuas lwm txoj haujlwm ntawm Dicer hauv tib neeg lub hlwb nrog rau hauv C.elegans, uas Dicer tau pom tias muaj kev koom tes hauv kev degradation ntawm ntau yam qauv. RNAs uas yav tas los tsis paub nrog lwm cov txheej txheem [9]

Tsis tas li ntawd, Drosha tuaj yeem tshem tawm cov kab plaub hau uas tau muab tso rau hauv mRNAs, ua rau lawv tsis muaj zog thiab yog li ncaj qha tswj mRNA qhia. Drosha tau pom tias tshem tawm mRNAs rau qhov sib txawv ntawm qhov tseem ceeb rau neurogenesis [10]. Tsis tas li ntawd, thaum kis kab mob, Drosha tau tshaj tawm tias yuav raug xa tawm mus rau hauv cytoplasm txhawm rau txhawm rau kis kab mob genomic RNA txhawm rau txhawm rau txhawm rau kis tus kabmob [101,102]. Phosphorylation thiab nuclear export ntawm Drosha kuj tshwm sim tom qab kub poob siab thiab oxidative kev nyuaj siab, impairing Drosha-mediated miRNA biogenesis [103]. Lwm cov txheej txheem tsim kho tshiab, hu ua formaldehyde crosslinking immunoprecipitation thiab sequencing (fCLIP-seq), tau nthuav tawm tias Drosha cleaves non-canonical substrates los ntawm non-miRNA loi rau hauv cov plaub hau luv luv, tsim cov RNAs me me [104] Cov txheej txheem siv PARCLIP-CLIP thiab txheeb xyuas qhov muaj peev xwm cuam tshuam ntawm miRNA-binding proteins thiab cov qauv RNAs hauv cov qauv ntaub so ntswg thiab hauv cov ntsiab lus ntawm cov kab mob uas muaj hnub nyoog [104]. Ua ke, cov txiaj ntsig ntawm cov kev tshawb fawb no muab cov kev tshawb fawb tshiab rau lub hom phiaj ntawm miRNA biogenesis Cheebtsam los hloov miRNA qhia, thiab tej zaum yuav tshiab mRNA lub hom phiaj, txhawm rau txhim kho cov kev sib txuas ntawm proteostasis hauv kev tshem tawm cov proteins lom thiab txo cov hnub nyoog ntsig txog cov protein sib xyaw.

9. Cov lus xaus

Lub hom phiaj tseem ceeb ntawm qhov kev tshuaj xyuas no yog los muab cov pov thawj txhawb nqa, raws li kev tshawb fawb tsis ntev los no, rau qhov kev cia siab tshiab tshiab uas miRNAs, thiab rau qee qhov miRNA-binding proteins, tuaj yeem ncaj qha tswj cov proteostasis, uas cuam tshuam rau kev loj hlob ntawm lub cev, thiab lawv tuaj yeem ua tau. kuj tseem siv tau los ua cov cim ntawm cov ntaub so ntswg noj qab haus huv rau kev sib piv nrog cov kab mob uas muaj hnub nyoog. Qhov tseem ceeb, miRNA lub hom phiaj cov noob nyob rau hauv proteostasis-txog degradation txoj hauv kev xws li UPS thiab ALP systems zoo li muaj cov ntaub so ntswg tshwj xeeb hauv cov tsiaj txhu hauv lub hlwb thiab cov pob txha pob txha thaum laus, hla ntau hom kab mob. Tsis tas li ntawd, lub luag haujlwm ntawm kev tswj hwm miRNA hauv cov hnub nyoog ntsig txog kev ua haujlwm tsis zoo ntawm cov protein degradation thiab tshem tawm cov txheej txheem tau dhau los ua pov thawj ntau dua nyob rau hauv cov kev tshawb fawb tsis ntev los no ntawm cov tsiaj hauv lub hlwb thiab cov nqaij pob txha.muab cistancheRaws li cov kev tshawb pom uas qhia tau hais tias miRNA-mediated proteostasis kev cai thaum lub sij hawm mammalian laus, peb theorize hais tias yav tom ntej kev tshawb fawb yuav tsum tshawb nrhiav ib tug ncaj causal kev sib raug zoo ntawm protein aggregation thiab miRNA dysregulation nyob rau hauv lub ntsiab lus ntawm ob qho tib si noj qab nyob zoo laus thiab hnub nyoog-txog pathological neurodegeneration thiab nqaij atrophy, uas. tau sawv cev rau hauv daim duab 2. Txij li thaum muaj qee qhov sib tshooj miRNA cov ntaub ntawv hloov pauv hauv ob qho tib si thiab cov kab mob pathological ntawm kev laus, lub peev xwm los hloov cov miRNAs, tshwj xeeb tshaj yog nce qib ntawm miRNAs uas lub hom phiaj tshem tawm cov protein ntau thiab cov noob caj noob ces muaj feem cuam tshuam rau yav tom ntej. anti-aging therapeutic tswv yim.

Sau Kev Koom Tes: Kev Tsim Nyog, SF, VM, ARS thiab MAS; kev sau ntawv—kev npaj ua ntej, SF; kev sau ntawv—kev tshuaj xyuas thiab kho, SF, VM., MF, AR, GM, ARS thiab MAS visualization, SFand VM; cov peev txheej, GM, A.RS.and MAS; kev saib xyuas, A.RS.and M.ASS, kev nrhiav nyiaj txiag, GM, ARS thiab MASSA Txhua tus kws 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 tau txais nyiaj los ntawm PORTUGUESE FOUNDATION FOR SCIENCE THIAB TECHNOLOGY (FCT) thiab FEDER (FUNDO EUROPEU DE DESENVOLVIMENTO REGIONAL) dhau los ntawm COMPETE2020, PROGRAM FOR COMPETITIVENESS AND-INTERGATION (2) FEDER-022184;WISDOM: POCI-0145-FEDER-029843); MEDICIS(CENTRO-01-0246-FEDER-000018}); thiab project "Piloto para an elaboration de uma estrategia e uma rede regional para a medicine personalized/precisao"Grant(CENTRO-08-5864-FSE{{9}) }).

Lub tsev tshawb fawb iBiMED tau txais kev txhawb nqa los ntawm FCT (UID/BIM/04501/2020). SF thiab MF tau txais kev txhawb nqa ncaj qha los ntawm FCT cov nyiaj pab (SFRH / BD / 148323 / 2019 thiab SFRH / BD / 131736 / 2017).

Kab lus no yog muab rho tawm los ntawm Int. J. Mol. Sci. 2022, 23, 3232. https://doi.org/10.3390/ijms23063232 https://www.mdpi.com/journal/ijms