Endogenous Mechanisms Of Neuroprotection: Kom Boost lossis Tsis Ua Part 1

Abstract:

Cov hlwb postmitotic, zoo li neurons, yuav tsum nyob mus ib txhis. Vim li no, cov kab mob / cellshave hloov zuj zus nrog cov txheej txheem kho tus kheej uas tso cai rau lawv kom muaj lub neej ntev.

Neurons yog lub hauv paus units uas tsim los ntawm tib neeg lub hlwb. Lawv xa cov ntaub ntawv los ntawm cov teeb liab hluav taws xob thiab txuas peb txoj kev xav thiab kev nco nrog lub ntiaj teb sab nraud. Kev nco yog hais txog lub peev xwm ntawm tib neeg los khaws thiab nco qab cov ntaub ntawv sab nraud los ntawm kev nkag siab, kev paub, thiab kev xav, thiab cov neurons yog ib feem tseem ceeb ntawm cov txheej txheem no.

Raws li cov neeg muaj hnub nyoog, tus naj npawb thiab kev ua haujlwm ntawm neurons maj mam txo qis, uas cuam tshuam rau qib ntawm kev nco. Yog li ntawd, peb yuav tsum txhawb nqa kev noj qab haus huv ntawm cov neurons thiab kev nco qab los ntawm kev tswj hwm tus cwj pwm zoo thiab kev noj qab nyob zoo.

Ua ntej tshaj plaws, kev tswj hwm tus cwj pwm zoo yog ib txoj hauv kev zoo los txhim kho kev ua haujlwm neuronal. Tus cwj pwm zoo tuaj yeem txhawb lub hlwb kom tso cov tshuaj zoo sib xws xws li dopamine thiab catecholamines, yog li txhawb kev ua haujlwm neuronal thiab txhim kho kev nco.

Qhov thib ob, kev tswj hwm tus cwj pwm noj qab haus huv kuj tseem ceeb rau kev noj qab haus huv ntawm cov neurons. Qee qhov kev tawm dag zog thiab kev tawm dag zog tuaj yeem txhawb nqa cov ntshav ncig thiab cov pa oxygen, uas pab txhim kho cov haujlwm thiab nco txog qib ntawm cov neurons. Tsis tas li ntawd, kev noj zaub mov zoo kuj tseem tuaj yeem muab cov neurons nrog kev noj zaub mov txaus thiab txhawb kev txhim kho kev nco.

Nyob rau hauv luv luv, kev sib raug zoo ntawm neurons thiab nco yog inseparable. Kev tuav tus cwj pwm zoo thiab kev noj qab nyob zoo yog txoj hauv kev zoo los txhim kho kev ua haujlwm neuronal thiab kev nco. Cia peb tuav tus cwj pwm zoo, ua tus cwj pwm zoo, thiab tsim kom muaj lub neej zoo siab, noj qab nyob zoo, thiab muaj zog ua ke. Nws tuaj yeem pom tias peb yuav tsum txhim kho kev nco. Cistanche tuaj yeem txhim kho kev nco zoo vim tias nws yog cov khoom siv tshuaj suav tshuaj suav nrog ntau yam tshwj xeeb, ib qho ntawm kev txhim kho kev nco. Cov nyhuv ntawm Cistanche yog los ntawm ntau yam khoom xyaw uas nws muaj, nrog rau tannic acid, polysaccharides, flavonoid glycosides, thiab lwm yam. Cov khoom xyaw no tuaj yeem txhawb lub hlwb kev noj qab haus huv ntau txoj hauv kev.

Nyem paub 10 txoj hauv kev los txhim kho kev nco

Kev tshawb pom kev ua haujlwm ntawm neuroprotectors nyob rau xyoo tas los no tau tsom mus rau kev thaiv cov kab mob pathophysiological uas ua rau muaj kev poob qis hauv neurodegeneration.

Hmoov tsis zoo, tsuas yog ob peb lub tswv yim los ntawm cov kev tshawb fawb no tuaj yeem ua rau qeeb lossis tiv thaiv neurodegeneration. Muaj cov pov thawj txaus ntseeg uas qhia tau hais tias pom zoo rau kev kho tus kheej cov txheej txheem uas cov kab mob / cov cell endogenously muaj, feem ntau hu ua cellular resilience, tuaj yeem arm neurons thiab txhawb lawv tus kheej kho.

Txawm hais tias kev txhim kho cov txheej txheem no tseem tsis tau txais kev saib xyuas txaus, cov txheej txheem no qhib txoj hauv kev tshiab los tiv thaiv kev tuag neuronal thiab ameliorate neurodegeneration. Ntawm no, peb hais txog lub ntsiab endogenous mechanisms ntawm kev tiv thaiv thiab piav qhia txog lawv lub luag haujlwm hauv kev txhawb nqa neuron survivalduring neurodegeneration.

Ntsiab lus: autophagy; cellular resilience; endogenous mechanisms; neuroprotection; neuronalsurvival; unfolded protein teb.

1. Cov txheej txheem Neurodegenerative

Nrog nce lub neej expectancy nyob rau hauv cov teb chaws tsim, ntau zaus ntawm cov kab mob neurodegenerative xws li Alzheimer's disease (AD), Parkinson's disease (PD) los yog Huntington'sdisease (HD), los yog hnub nyoog poob ntawm peb lub paj hlwb kev ua tau zoo, yuav muaj ntau ntxiv.

Txawm hais tias muaj ntau cov ntaub ntawv pov thawj qhia tau hais tias cov kab mob no muaj cov kab mob neuronal, astroglial, thiab microglial, qhov poob ntawm kev ua haujlwm txhua hnub yog tshwm sim los ntawm kev poob ntawm cov neuronal.

Vim lawv qhov kev poob qis, cov neurons yog cov kab mob postmitotics uas yuav tsum tau nyob mus ib txhis. Vim li no, lawv xav tau cov cuab yeej tiv thaiv zoo tshaj plaws los tiv thaiv sab nraud thiab sab hauv kev thuam, uas yuav ua rau lawv tuag.

Cov kev phom sij sab nrauv / sab hauv no yog kev raug mob los yog cov khoom siv excitotoxic, cov pa oxygen reactive (ROS), protein aggregates, thiab lwm yam tshuaj lom molecules.

Hmoov zoo, cov hlwb muaj cov tshuab hauv nruab nrog uas thaiv kev tuag los ntawm kev ua kom cov txheej txheem resilience los yog txhawb txoj kev tsim kho tshiab. Thaum cov tub ntxhais hluas neurons muaj kev ua haujlwm zoo ntawm cov txheej txheem tiv thaiv tus kheej, kev laus cuam tshuam rau lawv, ua rau cov neurons tsis muaj kev tiv thaiv. Nyob rau hauv tib txoj kev, dysfunctionality nyob rau hauv cov kev kho tus kheej mechanisms kuj tau piav txog cov kab mob inneurodegenerative.

Nyob rau hauv xyoo tas los no, kev siv zog loj heev tau nqis peev hauv kev tau txais cov kev kho tshiab thiab muaj txiaj ntsig zoo neuroprotective.

Txawm li cas los xij, lawv tau npaj rau lub hom phiaj pathophysiological mechanisms, uas thaum kawg tig mus rau hauv kev nrawm ntawm neuronal demise.Yog li ntawd, vim li cas ho tsis txhawb cov txheej txheem uas cov neurons muaj ib txwm muaj kom tau txais txoj hauv kev zoo neuroprotective?

Lub network tiv thaiv no yog tsav los ntawm kev sib tham ntawm cov txheej txheem ntawm tes sib txawv (piv txwv li, nthuav tawm cov lus teb ntawm cov protein (UPR), autophagy, thiab lwm yam), tab sis lawv hloov mus rau hauv tib txoj kev: tso cai rau lub cell hloov mus rau kev ntxhov siab thiab muaj sia nyob [1–3] .

Tsis ntev los no, peb tau txiav txim siab ib qho tshiab los tshawb pom cov tshuaj tiv thaiv neuroprotectants: decipher dab tsi molecular mechanisms neuronsengage tom qab ob lub paj hlwb sib txawv nrog kev sib txawv phenotypes, ciaj sia los yog tuag, uas qhia zoo sib xws nrog kev noj qab haus huv thiab neurodegeneration / laus. Ua li no, peb siv twoin vivo-raws li peripheral paj hlwb raug mob qauv uas ua raws li cov functionality los yog dysfunctionality ntawm endogenous mechanisms ntawm kev tiv thaiv.

Lawv provoke ob motoneuron (MN) tuag (root avulsion (RA)) los yog ciaj sia (distal axotomy (DA)), nyob ntawm seb qhov mob ntawm soma-kev puas tsuaj [2]. Nrog kev pab los ntawm cov qauv no thiab siv Systems Biology-raws li txoj hauv kev, peb tau lees paub tias kev tuag ntawm MNs tom qab RA sib piv nrog cov neuronal lossobserved nyob rau hauv cov kab mob neurodegenerative, thiab peb kuj tau piav qhia txog cov txheej txheem twg yog siv los ntawm MNs kom muaj sia nyob tom qab cov hlab ntsha raug mob [2 ].

Cov txheej txheem degenerative yog apoptosis, necrosis, anoikis, endoplasmic reticulum (ER) kev nyuaj siab, nucleolar stress, cytoskeletal rearrangements, thiab mitochondrial dysfunction, thaum cov tsav tsheb ntawm ciaj sia taus yog: ib tug yog UPR, lub tshav kub poob siab teb, lub autophagic txoj kev, ubiquitin. system, chaperonesystems, ER-koom nrog degradation machinery thiab antioxidant tiv thaiv (Table 1).

Interestingly, tag nrho cov txheej txheem no tau muab cais piav ntau xyoo dhau los thiab raug xa mus rau kev raug mob ua ntej (saib hauv qab).

Peb tau ua pov thawj tias kev txhawb nqa cov txheej txheem endogenous ntawm neuroprotection los ntawm kev kho tshuaj kho mob tso cai rau MN kom muaj sia nyob hauv cov xwm txheej sib txawv, xws li ntau hom mus rau ntau theem ntawm kev loj hlob [23,54,55].

2. Thawj Pov Thawj ntawm Endogenous Mechanisms: Pre-Conditioning

Cov teebmeem phenotypic ntawm endogenous mechanisms ntawm kev tiv thaiv tau piav 40 xyoo dhau los. Xyoo 1986. Murry et al. piav qhia tias sublethal physiological kev nyuaj siab, tseem hu ua preconditioning raug mob, txhim khu cov ntaub so ntswg rov qab nyob rau hauv lub plawv [56]. Los ntawm no, cov txheej txheem kho mob no kuj tau pom hauv lub hlwb thiab tus txha caj qaum (SC) [57].

Piv txwv li, cov lus teb ntawm tes tau pom tom qab raug mob los yog thaum lub sij hawm lub plawv rov qab los, qhov chaw tsim khoom ntawm ROS lossis extracellular vesicles feem, drivesfunctional recovery [58–60]. Kuj ceeb tias, kev kho mob ua ntej ntawm ib lub cev muaj zog tiv thaiv lwm tus los ntawm kev raug mob [61]. Ob peb qhov tshwj xeeb effectors yog lub luag haujlwm rau cov teebmeem no.

Tom qab kev raug mob ua ntej, kev tsim cov neeg sib txawv sib txawv (nitric oxide lossis ROS) yuav qhib txoj hauv kev taw qhia phosphatidylinositol 3-kinase (PI3K) / Proteinkinase B (AKT), Protein kinase C (PKC), thiab lwm yam kev taw qhia uas yuav hloov pauv. yam xws li Hypoxia-inducible factor 1-alpha (Hif1-) lossis NF-κB.

Cov no yuav ua rau kev tsim cov nitric oxide synthases (iNOS), cov proteins kub-poob siab (HSPs), thiab cyclooxygenase-2 (COX-2), uas tau piav qhia tias yog "end effectors", thiab yuav txhawb kev tiv thaiv. cov nyhuv nyob rau hauv cov ntaub so ntswg tiv thaiv yav tom ntej insults [61].

Ua ke, cov kev tshawb fawb no qhia tias cov kab mob / hlwb muaj cov txheej txheem tiv thaiv endogenous, thiab kev txhawb nqa lawv yuav yog ib qho kev kho mob zoo.

3. Endogenous Mechanisms ntawm Neuroprotection

3.1. Fine-Tuning Autophagy

Neurons xav tau kev rov ua dua tshiab ntawm cov ntaub ntawv hauv lub cev kom tswj tau homeostasis. Macro-autophagy, tom qab ntawd hu ua autophagy, yog ib qho kev sib koom ua ke ntawm molecular network hauv eukaryotic hlwb uas ua raws cov ntsiab lus cytoplasmic los ntawm lysosomaldegradation.

Txawm hais tias cov txheej txheem degradation no tau pib pom tsuas yog kev tshaib plab xwb, kev tshawb fawb tsis ntev los no tau pom tias cov hlwb muaj theem pib ntawm autophagy los tswj cov protein homeostasis.

Cov qib basal no yog qhov tseem ceeb rau kev saib xyuas axonal thiab kev ciaj sia ntawm neurons nyob rau hauv ib txwm muaj [62,63]. Kev ua haujlwm autophagic flux yog cov txheej txheem sib koom ua ke los ntawm ntau yam autophagy-related (ATG) noob, kinases, thiab lwm yam kev tswj hwm cov protein. Lawv txhua tus ua hauj lwm ua ke los tsim kho qhov pib, nucleation, elongation, kaw, thiab fusion ntawm autophagosomes nrog lysosomes kom degrade cytosolic load [64].

Kev txo qis ntawm autophagy yog pom nyob rau hauv hippocampus thaum lub sij hawm laus, thaum muaj kev txhim kho ntawm nws cov qib pab txhawb kev tsim cov cim tshiab [65].

Kev ua haujlwm tsis zoo autophagy hauv neurons yog txuam nrog neurodegeneration, thaum ua kom autophagy ua rau neuroprotection [5,54]. Kev hloov pauv ntawm cov proteins uas cuam tshuam txog cov theem pib thiab elongation tau pom nyob rau hauv amyotrophic lateral sclerosis (ALS) [66,67], thiab inducers ntawm autophagy, xws li rapamycin, exert neuroprotection tom qab cerebral ischemia, traumatic hlwb raug mob (TBI), thiab AD [68–70].

Cov neuron-specificknockout (KO) ntawm ATG5 los yog ATG7 ua rau neurodegeneration, tsub zuj zuj ntawm cytoplasmicinclusion lub cev, thiab kev tuag ntawm neurons [62,71], thaum lawv overexpression muaj txiaj ntsig hauv amodel ntawm PD [4].

Thaum kawg, p62, uas tswj hwm tus nqi hauv autophagosome thiab playsa lub luag haujlwm tseem ceeb hauv cov theem kawg ntawm kev tsim autophagosome, yog neuroprotective nyob rau hauv yoov qauv characterized los ntawm cov protein aggregates, uas yog lub cim ntawm cov kab mob neurodegenerative [6].

Ntau qhov kev tshawb fawb tau qhia txog kev sib sau ntawm autophagosomes thiab autolysosomesduring neurodegeneration, qhia tias autophagy yog overactivated thiab yuav ua rau tuag taus.

Aberrant tsub zuj zuj ntawm autophagic txheej txheem nyob rau hauv lub cytoplasm tej zaum yuav tshwm sim los ntawm lysosomal dysfunction, es tsis overactivated autophagy [72]. Autophagyis tau pib zoo tom qab TBI, tab sis autophagosomes tsis raug tshem tawm vim lysosomaldysfunction, ua rau tsis muaj kev kho mob autophagy uas txhawb kev tuag neuronal [73].

Cov kev tsis ua haujlwm lysosomal no kuj pom tom qab raug mob qaum qaum (SCI), hamperingfunctional recovery [74]. Ib qho zoo sib xws hauv kev tshem tawm ntawm autophagosomes kuj tau piav qhia hauv cov kab mob neurodegenerative (piv txwv li, tib neeg lub hlwb ntawm AD) [75].

Kev sib koom ua ke ntawm tag nrho cov pov thawj no qhia tias txhim kho qhov kev daws teeb meem ntawm autophagy tuaj yeem tiv thaiv kev tiv thaiv.Platt tsis ntev los no tau qhia txog kev kho mob ntawm kev txhim kho cov haujlwm ntawm lysosomalproteins los tiv thaiv neurodegeneration [76].

Lub overexpression ntawm transcription factorEB (TFEB), uas modulates ib tug transcriptional network tseem ceeb rau lysosome biogenesisand muaj nuj nqi, tau txhawb neuroprotective teebmeem nyob rau hauv ib tug nas qauv ntawm PD [7] thiab ADmice qauv [8].

Qhov induction ntawm autophagy tsis zoo li peb xav. Txawm hais tias nws yog ib qho kev tiv thaiv canonical, nws cov tshuab lossis overactivation tuaj yeem pab txhawb kev tuag ntawm tes [77,78].

Inhibition ntawm autophagy tom qab raug rau tib neeg prions txo cov neuronal puas tsuaj, qhia tias induction ntawm autophagy kuj ua rau tuag [79], thiab txo autophagy pib txhawb kev ua haujlwm rov qab los ntawm SC hemisection, tiv thaiv apoptosis, thiab txo cov pyramidaldeath tom qab ischemia hauv neonatal thiab cov laus nas [80] 82] ib.

Yog tias peb tsom mus rau axotomized neurons, thaiv autophagy yog neuroprotective rau rubrospinal ones [80], thaum nce qib ntawm ATG5 tiv thaiv txha caj qaum MNs [5]. Ntxiv cov kev tsis sib haum xeeb, cov qog nqaij hlav cancer kho nrog kev kho mob ua kom autophagy kom kov yeej kev kho mob apoptotic tuag, thaum MN-dependent autophagy inhibits apoptosis [54].

Tsis tas li ntawd, ATGs kuj ua rau neuronaldeath. ATG5 poob nws lub peev xwm pro-autophagic thaum cleaved, txav nws cov haujlwm mus rau qhov induction ntawm cell tuag [83-85]. Beclin1 muaj cov tshuaj tiv thaiv apoptotic nyob rau hauv cov xwm txheej zoo li qub, tab sis nws qhov cleavage ntawm C-terminus sensitizes lub hlwb rau apoptotic signals [9].

Yog li ntawd, muaj ib tug crosstalk ntawm ob lub cellular txheej txheem, thiab lub hlwb muaj peev xwm redirectthem kom lawv muaj feem muaj sia nyob mus tiv nrog cov kev thuam [83].Yog li, dab tsi yog qhov tseem ceeb rau neuroprotection? Boosting lossis thaiv autophagy?

Finetuning yog cov lus teb [86]. Induction ntawm ib tug nplua-tuned autophagy yields muaj txiaj ntsig los ntawm (i) tshem tawm cov uas tsis yog-functional proteins/organelles, (ii) tso cai rau lub cell kom nyeem tau qhov teeb meem tshiab, thiab (iii) degrading teeb meem xws li mob los yog apoptoticinducers [87,88] , uas kho neuronal demise.

Txawm li cas los xij, qhov no autophagy yuav tsum tau qhib rau hauv lub qhov rais tshwj xeeb ntawm lub sijhawm, tsis txhob muaj kev puas tsuaj ntau dhau uas ua rau cov cell tuag.

Thaum kawg, autophagy kuj muaj cov haujlwm uas tsis yog-canonical / degradative, xws li kev hloov pauv ntawm cov lus teb inflammatory, tsim kev nco tshiab [65], kev saib xyuas ntawm synaptic homeostasis [89], thiab kev thauj khoom hauv lub cell [90]. Yog li, kev ua tiav ntawm nws yuav ua rau tsis muaj kev puas tsuaj rau lub paj hlwb thiab / lossis neurons.

3.2. Tackling qhov Sexy Part ntawm Unfolded Protein teb

Neurons yog qhov tsis tshua muaj siab rau misfolded proteins thiab aggregates.

Lub ER yog lub luag haujlwm rau cellular proteostasis, uas yog kev sib txuas, folding, thiab sorting ntawm cov proteins.Txhua yam kev hloov pauv hauv nws lub cev yuav ua rau muaj kev sib txuam ntawm misfolded proteins, inducingER stress thiab activating ER-overload teb (ERO), ER-koom nrog. degradation (ERAD) txoj hauv kev, lossis UPR, uas yog cov lus teb tau zoo heev ntawm tes.

Kev hloov pauv hauv kev faib tawm thiab morphology ntawm ER thiab UPR tau pom nyob rau hauv cov kab mob neurodegenerative [91-93] thiab thaum cov neuron raug cais tawm tom qab raug mob paj hlwb [16,94].

Binding immunoglobulin protein (BIP), tseem hu ua GRP78, yog ER-neeg nyob chaperonethas yog lub ntsiab sensor ntawm UPR. Nyob rau hauv lub xeev tsis muaj zog, BIP tseem nyob rau hauv peb qhov loj UPR effectors: RNA-activated protein kinase-zoo li ER kinase (PERK) uas inducesC/EBP homologous protein (CHOP), inositol-yuav tsum tau protein-1 alpha ( IRE1 ), whichsplices X-box binding protein 1 (Xbp1) mRNA, thiab activating transcription factor{10}}alpha (ATF6) [95,96].

Thaum BIP pom misfolded proteins, cov transducers yog activated thiab tsav kev hloov nyob rau hauv cov noob qhia ntawm cov proteins tshwj xeeb (piv txwv li, chaperones, transcriptionfactors) kom lub cell lub peev xwm kom raug folded proteins los ntawm modulatinggene qhia, txhim khu lub clearance ntawm misfolded proteins ' clearance, los yog inhibitingprotein. synthesis, cia lub cell hloov mus rau kev ntxhov siab thiab ciaj sia [97].

Raws li cov ntaub ntawv pov thawj, BIP overexpression nyob rau hauv dopamine neurons nce lawv txoj sia nyob, thaum nws downregulation induces tuag ntawm nigral dopamine neurons [10]. Tsis tas li ntawd, BIP +/- miceshow accelerated propagation ntawm prion pathogenesis [98].

Zuag qhia tag nrho, UPR kev hloov pauv tuaj yeem tiv thaiv kev cuam tshuam ntawm neurodegeneration [94], raws li kev tshuaj xyuas tsis ntev los no los ntawm peb pab pawg [99].UPR kev ua haujlwm yog ib qho kev tshwm sim ntxov hauv cov kab mob neurodegenerative, thiab nws qhov kev hloov kho meej muaj txiaj ntsig zoo rau kev mob pathology [100,101]. Txawm hais tias UPR tuaj yeem ua asan endogenous mechanism ntawm kev tiv thaiv ntawm tes, nws (dhau) ua kom txhawb nqa apoptosis [102] (ie, PERK axis muaj peev xwm tiv thaiv apoptotic [91]).

Tsis tas li ntawd, cov pov thawj tsis ntev los no qhia tau hais tias kev sib txawv ntawm ER yuav qhib qhov sib txawv ntawm 3 ceg ntawm UPR, qhia tias kev sib koom ua ke ntawm lawv tsis yog ib txwm muaj. Yog li ntawd, lub xov tooj ntawm tes muaj ib qho kev pab cuam los teb rau ib qho kev thuam tshwj xeeb.

Piv txwv li, CHOPblockage lossis Xbp1 overexpression nce neuron ciaj sia tom qab cov hlab ntsha raug mob, qhia tias txhua ceg muaj lub luag haujlwm sib txawv hauv neuron tuag [16].

Kev ua kom ntxov ntawm PERK tom qab lub hlwb raug mob exerts neuroprotection, thaum lub sij hawm qhov taw qhia los ntawm txoj kev no exacerbates cell poob [11]. Overexpression orpharmacological PERK activation txo Tau pathology [12], thaum averting nws sustainedactivation diminishes neuronal tuag [13] thiab txhim kho lub hnub nyoog txog kev nco poob [14].

Qhov inhibition ntawm PERK nyob rau hauv astrocytes qeeb neuronal poob nyob rau hauv ib tug prion-kab mob nyob rau hauv vivo qauv.Interestingly, PERK activation nyob rau hauv astrocytes cuam tshuam lub secretome, hloov nws synaptogenic muaj nuj nqi thiab ua rau synaptic poob [15].

Tib cov kws sau ntawv tau piav qhia tias cov txheej txheem tseem ceeb hauv qab no koom nrog qhov cuam tshuam ntawm PERK yog txoj hauv kev sib txuas ntawm cov xov tooj ntawm tes, uas hla UPR nrog cov anoikis (saib hauv qab no, Tshooj 3.4).

Kev ua kom muaj kev hloov pauv hloov pauv 5 (ATF5) theem ncaj qha nyob ntawm qhov ua kom PERK / eukaryotic translation pib qhov tseem ceeb 2a (eIF2a). ATF5 tau raug txuas ncaj qha rau cov neurons uas muaj zog dua rau kev tuag hauv tib neeg qaug dab peg [26].

Txawm li cas los xij, cov txiaj ntsig tom qab ntawm cov teebmeem no tsis meej. ATF5 induces cov kev qhia ntawm ob anti-apoptotic effectors (saib hauv qab), B-cell lymphoma 2 (Bcl-2) thiab induced myeloidleukemia cell txawv protein (Mcl-1) [103], uas yuav inhibit apoptosis.

ATF5 kuj hloov kho lub hom phiaj ntawm rapamycin (mTOR) nyob rau hauv cov ntaub so ntswg uas tsis yog neuronal, uas yog lub ntsiab modulator ntawm autophagy, interrelated UPR thiab autophagy.

Kev ua kom IRE1 ua kom lub siab tsis ua haujlwm [17], thiab nws cov nyhuv downstream Xpb1 txhawb kev tiv thaiv plawv [18], thiab neuroprotection hauv AD, PD, thiab tom qab mob stroke [19–21].

Strikingly, kev tshawb fawb hauv ntshav qab zib thiab ischemia-induced retinopathy tau pom tias kev tiv thaiv ntawm UPR yog kho los ntawm Xbp1 [22]. Txawm li cas los xij, kev ua kom ntev ntev ntawm IRE1 ceg yuav ua rau phosphorylation ntawm cov qog necrosis factor-a (TNF- ) receptor-associated factor 2 (TRAF2), ua rau apoptotic cell tuag nyob rau hauv ntau txoj kev [104–106].

Ectopic overexpression ntawm Ire1 yuav ua rau autophagy-dependent neuronal tuag hauv PD Drosophila qauv [107]. Yog li ntawd, kev hloov kho ntawm IRE1 -Xbp1 thaum lub qhov rais tshwj xeeb tuaj yeem tiv thaiv [108].

Peb tsis ntev los no tau piav qhia tias NeuroHeal pharmacological kev kho mob lossis sirtuin1 (SIRT1) overexpression induces ciaj sia taus ntawm MN tom qab cov hlab ntsha raug mob, thiab ua rau kom muaj cleaved ATF6 thaum txo IRE1 phosphorylation [23].

Pharmacological activation ntawm ATF6 induces kev tiv thaiv nyob rau hauv txawv ischemia qauv los ntawm activating proteostasis [24], thiab cov blockage ntawm no transcription factor muaj deleterious teebmeem.

Hauv kev nthuav dav, ATF6 modulatesantioxidant-response-related proteins 'qhia, modulating ROS hormesis [109].Force qhia ntawm ATF6 txhim kho cov txiaj ntsig ua haujlwm tom qab mob stroke, thiab cov kws sau ntawv qhia tias cov nyhuv no tuaj yeem kho los ntawm induction ntawm autophagy [25].

Yog li, dab tsi yog kev kho mob nthuav dav, qhib, lossis txo qis UPR? Kev ua kom cov ceg tshwj xeeb ntawm UPR yog lub ntsiab lus tseem ceeb. Kev ua kom meej meej ntawm UPR tuaj yeem txhawb nqa kev tiv thaiv los ntawm kev pab lub cell los kho cov kab mob proteostasis.

Txawm li cas los xij, lub tswv yim no yuav tsum tau ceev faj vim tias yog tias muaj kev ntxhov siab tsis tu ncua thiab proteostasis tsis rov qab los, UPR ua rau neuronal apoptosis uas yog kho los ntawm PERK lossis IRE1 ceg [110]. Tsis tas li ntawd, UPR tseem txuas nrog autophagy thiab vice versa.

BIP mediates cov lus teb autophagic, txhawb kev muaj sia nyob neuronal [111]. Thaum kawg, 3 ceg ntawm UPRmodulate qhov kev hloov pauv ntawm ATGs [112], qhia txog kev sib txuas ntawm cov txheej txheem cellular.

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