Dab tsi yog Endogenous Mechanisms Ntawm Neuroprotection?

Hu rau:joanna.jia@wecistanche.com/ WhatsApp: 008618081934791

cistanche cov txiaj ntsig tuaj yeem pab nrog neuroprotection

Sara Marmolejo-Martinez-Artesero 1, Caty Casas 1, † thiab David Romeo-Guitart1,2,*

1 Department of Cell Biology, Physiology, thiab Immunology, Institut de Neurosciences (INc),

Universitat Autonoma de Barcelona (UAB), Bellatera, 08193 Barcelona, ​​Spain; Sara.Marmolejo@uab.cat

2 Laboratory "Hormonal Regulation of Brain Development and Functions"—Team 8, Institut Necker Enfants-Malades (INEM), INSERM U1151, Université Paris Descartes, Sorbonne Paris Cité,

75015 Paris, Fabkis

* Cov ntawv xov xwm: david.romeo-guitart@inserm.fr; Tel.: plus 33-01-40-61-53-57 † Tuag 29 Lub Rau Hli 2020.

Abstract: Postmitotic hlwb, zoo li neurons, yuav tsum nyob mus ib txhis. Vim li no, cov kab mob / hlwb tau hloov zuj zus nrog cov txheej txheem kho tus kheej uas tso cai rau lawv kom muaj lub neej ntev. Kev tshawb pom kev ua haujlwm ntawm neuroprotectors nyob rau xyoo tas los tau tsom mus rau kev thaiv cov txheej txheem pathophysiological uas ua rau muaj kev puas tsuaj 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 tsis txaus ntseeg uas qhia tau hais tias pom zoo rau kev kho tus kheej cov txheej txheem uas 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 kev kho 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 hauj lwm nyob rau hauv txhawb neuron ciaj sia taus thaum lub sij hawm neurodegeneration.

Ntsiab lus: autophagy; cellular resilience; endogenous mechanisms; neuroprotection; neuronal ciaj sia; 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's disease (HD), los yog hnub nyoog txog kev poob ntawm peb lub paj hlwb kev ua tau zoo, yuav nce. Txawm hais tias muaj ntau cov ntaub ntawv pov thawj qhia tau hais tias cov kab mob no muaj cov tshuaj 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 hloov pauv tsawg, cov neurons yog cov hlwb postmitotic uas yuav tsum nyob mus ib txhis. Vim li no, lawv xav tau lub tshuab tiv thaiv lub cev muaj zog los tiv thaiv sab nraud thiab sab hauv kev thuam, uas yuav ua rau lawv tuag. Cov kev phom sij sab nraud / 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 khoom siv 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 ntawm cov kev kho tus kheej mechanisms kuj tau piav nyob rau hauv cov kab mob neurodegenerative.

Nyob rau hauv xyoo tas los no, kev siv zog loj heev tau nqis peev los tau txais cov kev kho mob neuroprotective tshiab thiab zoo. Txawm li cas los xij, lawv tau npaj rau lub hom phiaj pathophysiological mechanisms, uas thaum kawg hloov mus rau hauv kev nrawm ntawm neuronal demise. Yog li, vim li cas ho tsis txhawb cov txheej txheem uas cov neurons muaj ib txwm ua kom tau txais txiaj ntsig zoo neuroprotective mus kom ze?

Qhov kev tiv thaiv network no yog tsav los ntawm kev sib tham ntawm cov txheej txheem ntawm tes sib txawv (piv txwv li, cov lus teb tsis muaj protein ntau (UPR), autophagy, thiab lwm yam), tab sis lawv hloov mus rau hauv tib txoj kev: cia lub cell hloov mus rau kev ntxhov siab thiab muaj sia nyob [1–3] . Tsis ntev los no, peb tau txiav txim siab txog qhov laj thawj tshiab los tshawb pom cov tshuaj tiv thaiv kab mob neuroprotectants: decipher dab tsi molecular mechanisms neurons koom nrog tom qab ob lub paj hlwb sib txawv nrog cov phenotypes sib txawv, ciaj sia lossis tuag, uas sib piv nrog kev noj qab haus huv thiab neurodegeneration / laus. Ua li no, peb siv ob qho hauv vivo-based peripheral paj hlwb raug mob qauv uas ua raws li kev ua haujlwm lossis kev ua haujlwm tsis zoo ntawm cov txheej txheem endogenous ntawm kev tiv thaiv. Lawv provoke ob motoneuron (MN) kev tuag (hauv paus avulsion (RA)) los yog ciaj sia (distal axotomy (DA)), nyob ntawm seb qhov kev raug mob ntawm soma [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 qhia qhov sib xws nrog kev poob ntawm cov paj hlwb pom 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 raug mob paj hlwb. [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 raug UPR, lub tshav kub- shocks teb, autophagic txoj kev, lub ubi proteasome system, chaperone systems, ER-koom nrog degradation machinery thiab antioxidant tiv thaiv (Table 1). Interestingly, tag nrho cov txheej txheem no tau cais tau piav qhia ntau xyoo dhau los thiab raug xa mus rau kev raug mob ua ntej (saib hauv qab).

Table 1. Cov ntsiab lus ntawm cov proteins uas cuam tshuam rau txhua qhov endogenous mechanism ntawmneurotiv thaiv, nrog rau cov txheej txheem molecular uas lawv cov teebmeem tau kho.

Peb tau pom tias boosting no endogenous mechanisms ntawmneurotiv thaivlos ntawm kev kho tshuaj kho mob tso cai rau MN kom muaj sia nyob hauv cov xwm txheej sib txawv ntawm kev tuag, xws li los ntawm 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 plawv rov ua dua tshiab, qhov chaw tsim khoom ntawm ROS lossis extracellular vesicles feem, ua haujlwm rov qab ua haujlwm [58–60]. Kuj ceeb tias, kev kho mob ua ntej ntawm ib lub cev tshwj xeeb tiv thaiv lwm tus los ntawm kev raug mob [61]. Ob peb tus cwj pwm tshwj xeeb yog lub luag haujlwm rau cov teebmeem no. Tom qab kev raug mob ua ntej, kev tsim cov khoom sib txawv (nitric oxide los yog ROS) yuav qhib txoj kev taw qhia phosphatidylinositol 3-kinase (PI3K) / Protein kinase B (AKT), Protein kinase C (PKC), thiab lwm yam kev taw qhia uas yuav hloov pauv cov khoom hloov pauv xws li Hypoxia-inducible factor 1-alpha (Hif1-) lossis NF-kB. 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 nqa. kev tiv thaiv 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 hereafter hu ua autophagy, yog ib qho kev sib koom ua ke ntawm molecular network hauv eukaryotic hlwb uas nrhiav kev rov ua dua cov ntsiab lus cytoplasmic los ntawm lysosomal degradation. Txawm hais tias qhov kev degradation no tau pib pom tsuas yog nyob rau hauv kev tshaib kev nqhis, kev tshawb fawb tsis ntev los no tau pom tias cov hlwb muaj cov theem pib ntawm autophagy los tswj cov protein homeostasis. Cov qib basal no yog qhov tseem ceeb rau kev saib xyuas axonal thiab kev muaj sia nyob ntawm cov neurons nyob rau hauv ib txwm muaj [62,63]. Kev ua haujlwm autophagic flux yog ib txoj kev sib koom ua ke los ntawm ntau hom autophagy-related (ATG) noob, kinases, thiab lwm yam kev tswj hwm cov protein. Lawv txhua tus ua haujlwm ua ke los tsim kho qhov pib qhov tseeb, nucleation, elongation, kaw, thiab fusion ntawm autophagosomes nrog lysosomes kom degrade cytosolic load [64]. Kev txo qis ntawm autophagy yog pom nyob rau hauv lub hippocampus thaum lub sij hawm laus, thaum lub reestablishment ntawm nws cov theem pab txhawb kev tsim ntawm tshiab nco [65]. Kev puas tsuaj los yog tsis ua haujlwm autophagy hauv neurons yog txuam nrog neurodegeneration, thaum ua kom autophagy tsimneurotiv thaiv[5,54]. Kev hloov pauv hauv cov proteins uas cuam tshuam rau cov theem pib thiab elongation tau pom nyob rau hauv amyotrophic lateral sclerosis (ALS) [66,67], thiab inducers ntawm autophagy, xws li rapamycin, exert.neurotiv thaivTom qab cerebral ischemia, traumatic hlwb raug mob (TBI), thiab AD [68–70]. Cov neuron tshwj xeeb knockout (KO) ntawm ATG5 los yog ATG7 ua rau neurodegeneration, tsub zuj zuj ntawm cytoplasmic inclusion lub cev, thiab kev tuag ntawm neurons [62,71], thaum lawv overexpression muaj txiaj ntsig hauv tus qauv ntawm PD [4]. Thaum kawg, p62, uas tswj hwm tus nqi hauv autophagosome thiab ua lub luag haujlwm tseem ceeb hauv cov theem kawg ntawm kev tsim autophagosome, yog neuroprotective hauv cov qauv yoov uas muaj protein ntau, uas yog lub cim ntawm cov kab mob neurodegenerative [6].

Ntau qhov kev tshawb fawb tau qhia txog kev sib sau ntawm autophagosomes thiab autolysosomes thaum lub sij hawm neurodegeneration, qhia tias autophagy yog overactivated thiab tej zaum yuav ua rau neuronal tuag. Aberrant tsub zuj zuj ntawm autophagic txheej txheem nyob rau hauv lub cytoplasm yuav tshwm sim los ntawm lysosomal dysfunction, es tsis overactivated autophagy [72]. Autophagy tau pib ua haujlwm zoo tom qab TBI, tab sis autophagosomes tsis raug tshem tawm vim lysosomal tsis ua haujlwm, ua rau tsis muaj kev kho mob autophagy uas txhawb nqa kev tuag ntawm neuronal [73]. Cov kev tsis ua haujlwm lysosomal no kuj pom tom qab raug mob qaum qaum (SCI), cuam tshuam kev ua haujlwm rov qab [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 qhia txog txoj kev kho mob ntawm kev txhim kho txoj haujlwm ntawm lysosomal proteins los tiv thaiv neurodegeneration [76]. Lub overexpression ntawm transcription factor EB (TFEB), uas modulates ib tug transcriptional network tseem ceeb rau lysosome biogenesis thiab muaj nuj nqi, tau txhawb neuroprotective teebmeem nyob rau hauv ib tug nas qauv ntawm PD [7] thiab ib tug AD nas 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 qhov kev puas tsuaj ntawm neuronal, qhia tias induction ntawm autophagy tseem tsav kev tuag [79], thiab txo autophagy pib txhawb kev ua haujlwm rov qab los tom qab SC hemisection, tiv thaiv apoptosis thiab txo cov pyramidal tuag tom qab ischemia hauv cov nas me me thiab cov laus. [80–82]. 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 kev tsis sib haum xeeb, cov qog nqaij hlav qog noj ntshav tau kho nrog tshuaj 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 muaj kev tuag neuronal. ATG5 poob nws lub peev xwm pro-autophagic thaum cleaved, txav nws cov haujlwm mus rau induction ntawm cell tuag [83–85]. Beclin1 muaj cov tshuaj tiv thaiv apoptotic nyob rau hauv ib txwm muaj mob, tab sis nws cov cleavage ntawm C-terminus sensitizes lub hlwb rau apoptotic signals [9]. Yog li ntawd, muaj kev sib tham ntawm ob lub xovtooj ntawm tes, thiab lub hlwb tuaj yeem hloov kho lawv kom lawv muaj feem muaj sia nyob los tiv thaiv kev thuam [83].

Yog li, dab tsi yog qhov tseem ceeb rauneurotiv thaiv? Boosting lossis thaiv autophagy? Kev kho kom zoo yog cov lus teb [86]. Induction ntawm fine-tuned autophagy yields cov txiaj ntsig zoo los ntawm (i) tshem tawm cov proteins/organelles uas tsis ua haujlwm, (ii) tso cai rau lub xov tooj ntawm tes los nyeem cov xwm txheej tshiab, thiab (iii) degrading cov teebmeem xws li mob khaub thuas lossis apoptotic inducers [87, 88], uas kho cov neuronal demise. Txawm li cas los xij, qhov autophagy no yuav tsum tau qhib rau hauv lub qhov rais tshwj xeeb ntawm lub sijhawm, zam dhau kev degradation uas ua rau cov cell tuag.

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

cistanche deserticola cov txiaj ntsig: tuaj yeem pab nrog kev tiv thaiv kab mob

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 cov synthesis, folding, thiab sorting ntawm cov proteins. Ib qho kev hloov pauv hauv nws qhov kev ruaj ntseg yuav ua rau muaj qhov sib txuam ntawm cov misfolded proteins, ua rau ER kev ntxhov siab thiab ua kom cov lus teb ER-overload (ERO), txoj hauv kev ER-associated degradation (ERAD), los yog UPR, uas yog ib qho kev txuag cellular teb. Kev hloov pauv hauv kev faib khoom 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 chaperone uas yog lub ntsiab sensor ntawm UPR. Nyob rau hauv lub xeev tsis muaj zog, BIP tseem nyob rau hauv peb lub ma-

jor UPR effectors: RNA-activated protein kinase-like ER kinase (PERK) uas induces C/EBP homologous protein (CHOP), inositol-yuav tsum tau protein-1 alpha (IRE1), uas splices X-box binding protein 1 (Xbp1) mRNA, thiab qhov ua kom muaj kev hloov pauv hloov pauv hloov pauv-6 alpha (ATF6) [95,96]. Thaum BIP pom misfolded proteins, cov transducers tau qhib thiab tsav cov kev hloov hauv cov noob qhia ntawm cov proteins tshwj xeeb (piv txwv li, chaperones, transcription factors) nrog rau lub hom phiaj ntawm kev ua kom lub cell muaj peev xwm ua kom raug cov proteins los ntawm kev hloov cov noob qhia, txhim kho qhov kev tshem tawm ntawm misfolded. proteins 'clearance, los yog inhibiting protein synthesis, cia lub cell hloov mus rau qhov kev nyuaj siab thiab ciaj sia [97]. Raws li ib qho pov thawj ntawm lub tswv yim, 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 ntxiv / − nas qhia nrawm nrawm ntawm prion pathogenesis [98]. Zuag qhia tag nrho, UPR kev hloov kho tuaj yeem tiv thaiv kev tiv thaiv ntawm neurodegeneration [94], raws li kev tshuaj xyuas tsis ntev los no los ntawm peb pab pawg [99]. UPR activation yog ib qho kev tshwm sim ntxov hauv cov kab mob neurodegenerative, thiab nws qhov kev hloov kho meej tau muaj txiaj ntsig zoo rau kev nce qib ntawm pathology [100,101]. Txawm hais tias UPR tuaj yeem ua raws li cov txheej txheem endogenous 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 qhov kev cuam tshuam 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 cell muaj ib tug tshwj xeeb kev pab cuam los teb rau ib tug tshwj xeeb insult. Piv txwv li, CHOP blockage lossis Xbp1 overexpression nce neuron ciaj sia taus tom qab paj hlwb raug mob, qhia tias txhua ceg muaj lub luag haujlwm sib txawv hauv neuron tuag [16].

cistanche nyob rau hauv hindi herba tuaj yeem pab nrog neuroprotection

Kev ua kom ntxov ntawm PERK tom qab lub hlwb raug mobneurotiv thaiv, thaum lub teeb liab txuas ntxiv los ntawm txoj kev no exacerbates cell poob [11]. Overexpression lossis pharmacological PERK activation txo Tau pathology [12], thaum averting nws qhov kev ua kom ruaj khov txo qis kev tuag neuronal [13] thiab txhim kho hnub nyoog ntsig txog kev nco poob [14]. Qhov inhibition ntawm PERK hauv astrocytes qeeb neuronal poob hauv prion-kab mob 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 hauv qhov cuam tshuam tsis zoo ntawm PERK yog txoj hauv kev sib txuas ntawm cov cellular matrix-cell adhesion, 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 txuas ncaj qha rau cov neurons uas muaj zog dua rau kev tuag hauv tib neeg mob qaug dab peg [26]. Txawm li cas los xij, cov txiaj ntsig tom qab ntawm cov teebmeem no tsis meej. ATF5 induces kev qhia ntawm ob anti-apoptotic effectors (saib hauv qab), B-cell lymphoma 2 (Bcl{20}}) thiab induced myeloid leukemia cell txawv protein (Mcl-1) [103], uas yuav inhibit. apoptosis. ATF5 kuj tau hloov kho lub hom phiaj ntawm rapamycin (mTOR) hauv cov ntaub so ntswg uas tsis yog neuronal, uas yog lub ntsiab modulator ntawm autophagy, cuam tshuam txog UPR thiab autophagy.

Ua kom IRE1 ua kom lub siab tsis ua haujlwm [17], thiab nws cov nyhuv qis qis Xpb1 txhawb kev tiv thaiv plawv [18],neurotiv thaivhauv AD, hauv 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 kev 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 raug mob paj hlwb, 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 blockage ntawm no transcription factor muaj deleterious teebmeem. Hauv kev nthuav dav, ATF6 modulates antioxidant-response-related proteins 'qhia, modulating ROS hormesis [109]. Kev quab yuam ntawm ATF6 txhim kho cov txiaj ntsig ua haujlwm tom qab mob stroke, thiab cov kws sau ntawv qhia tias qhov kev cuam tshuam no tuaj yeem kho los ntawm qhov induction ntawm autophagy [25].

Yog li, dab tsi yog qhov kev kho mob nthuav dav, ua kom muaj zog, 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 kev tiv thaiv los ntawm kev pab lub cell kom rov qab kho cov 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 UPR hloov pauv qhov kev hloov pauv ntawm ATG's [112], qhia txog kev sib txuas ntawm ob qho tib si ntawm tes.

3.3. "Tsis Hnub no" Apoptosis

Apoptosis yog caspase-dependent programmed cell death (PCD) uas tswj kev ncaj ncees ntawm cov cell plasma membrane thiab cov organelles [113]. Nws dysregulation yog ua rau ntau cov qog nqaij hlav, neurodegenerative lossis inflammatory pathologies. Caspase-induced tuag yog cov txheej txheem tswj tau zoo uas xav tau kev sib koom tes ntawm ntau tus neeg ua si kom ua rau lub cev tuag kawg [114]. Apoptosis zoo li kev tuag muaj nyob hauv Amyotrophic lateral sclerosis (ALS) nas qauv, AD, lossis PD, txawm hais tias tsis paub meej tias nws yog tus thawj tswj hwm ntawm neuronal demise [115]. Thaum lub sij hawm evolution, hlwb tau tsim ntau lub tswv yim los tiv thaiv lawv txoj kev tuag thaum nws tsis xav tau lossis kom tsis txhob muaj PCD ntxov ntxov. Cells tsuas yog ua rau muaj txiaj ntsig zoo apoptotic tuag thaum qhov sib npaug ntawm pro- lossis anti-apoptosis machinery thawb lawv mus rau kev tuag. Raws li peb cov qauv hauv vivo, peb pom tias RA induces apoptotic pathways tab sis kuj anti-apoptotic sawv daws yuav, thiab lawv cov nyiaj tshuav ua rau lwm txoj kev thiab tsis paub tuag uas tsis yog classical apoptosis [2]. Cov ntawv tshaj tawm kawg hauv daim teb qhia tias caspases kuj ua los ntawm kev hloov kho lub paj hlwb tsis txhawb kev tuag ntawm tes [116], thiab lawv cov haujlwm nyob ntawm nws txoj haujlwm subcellular. Yog li ntawd, cov ntaub ntawv nquag ntawm caspases uas pom nyob rau hauv cov ntaub so ntswg neurodegenerative tuaj yeem muaj lub luag haujlwm tsis muaj kev tuag thiab kev tuag neuron kawg yog los ntawm lwm yam kev tuag.

Apoptosis tuaj yeem cuam tshuam los ntawm txoj kev tiv thaiv apoptotic, uas tau tsav los ntawm peb tsev neeg cov protein: FLICE-inhibitory proteins, Bcl-2, thiab Inhibitors of Apoptosis Proteins (IAPs). IAPs exertneurotiv thaivnyob rau hauv tus qauv ischemia [27] lossis zam kev tuag ntawm MNs tom qab cov hlab ntsha raug mob thaum lub sij hawm cev xeeb tub [28]. IAPs tau npaj los ua lub luag haujlwm rau kev thaiv kev tuag ntawm neuronal tom qab axotomy thaum muaj hnub nyoog laus [29]. Nyob rau hauv tib txoj kev, ib qho kev hloov pauv tom qab ntawm X-txuas-IAP (XIAP), uas thaiv nws txoj haujlwm tiv thaiv caspase 3, tau piav qhia tias yog tus pab txhawb rau PD pathogenesis [117].

Ischemic preconditioning, uas ib feem txo qis kev cuam tshuam ntawm ischemia, ua los ntawm IAPs thiab ua kom cov hlwb muaj sia nyob tom qab caspase cascade ua kom [30]. IAPs kuj kho cov txiaj ntsig ntawm kev muaj sia nyob ntawm glial cell-derived neurotrophic factor (GDNF) ntawm MNs tom qab neonatal axotomy [28]. Lwm txoj hauv kev molecular uas zam kev tuag ntawm tes los ntawm kev hloov kho pro-apoptotic proteins yog extracellular signal-regulated kinases (ERK) thiab AKT. Hauv qhov kev nkag siab no, AKT txoj hauv kev tau piav qhia tias yog tus neeg muaj sia nyob los ntawm kev thaiv apoptosis [31]. AKT inhibits apoptosis inducer p53 los ntawm kev txhawb nqa nws cov degradation thiab yog li thaiv nws cov peev xwm pro-apoptotic [32–34]. Txwv tsis pub, caspases muaj peev xwm inhibit AKT los ntawm nws cov cleavage, uas taw qhia txog kev hloov kho kom zoo ntawm cell survival thiab tuag [118]. Ntawm qhov tod tes, AKT kev ua phosphorylates lub Forkhead box protein O (FOXO) cov ntaub ntawv hloov pauv. Lawv muaj feem cuam tshuam rau apoptosis [119] thiab lawv qhov kev hloov pauv hloov pauv ntawm cov cell muaj sia nyob [35]. AKT-dependent phosphorylation ntawm FOXOs zam nws txoj kev nkag mus rau hauv lub nucleus, tiv thaiv qhov induction ntawm pro-apoptotic genes xws li Bcl -2- interacting mediator of cell death (BIM) los yog Bcl-2 kaum cuaj-kilodalton-interacting protein 3 (Bnip3) [119–121]. Ntawm qhov tod tes, kev hloov pauv tom qab hloov pauv ntawm FOXO tau kho lawv cov kev sib txuas lus hauv lub xovtooj ntawm tes, txav mus rau autophagy induction tsis yog apoptosis [54,121–123]. Yog li ntawd, kev hloov kho tshwj xeeb ntawm FOXO tsev neeg yog ib txoj hauv kev tshiab los txhawb kev muaj sia nyob ntawm neuronal los ntawm inhibiting apoptosis [54,124].

Thaum kawg, kev ua haujlwm neuronal kuj yog ib qho kev txhawb nqa ntawm kev tiv thaiv apoptosis los ntawm NMDA-dependent anti-apoptotic genes 'upregulation [125,126]. Qee qhov kev hloov pauv cov noob no tso cai rau mitochondria ua rau muaj kev tiv thaiv ntau dua rau kev ntxhov siab [126], pab lub cell kom ciaj sia qhov kev thuam.

3.4. Reattaching los ntawm Anti-Anoikis

Kev sib cuam tshuam ntawm cov cell thiab extracellular matrix (ECM) yog qhov tseem ceeb rau nws txoj kev ua haujlwm zoo hauv cov ntaub so ntswg. Thaum qhov kev sib tham sib tham no yog averted, lub xov tooj ntawm tes tuag los ntawm PCD hu ua anoikis, uas qhia txoj hauv kev nrog apoptosis. Interestingly, qhov kev puas tsuaj ntawm intrinsic anoikis cov kev pab cuam confers malignancy rau qog hlwb, muab lawv txaus cellular resilience kom dim thiab rov mus rau lwm cov ntaub so ntswg tsis tuag [127,128]. Cov txiaj ntsig tseem ceeb ntawm cov kev sib cuam tshuam no yog cov integrin proteins, uas yog tsim los ntawm kev sib xyaw ua ke thiab subunits. Qhov kev sib xyaw ua ke no yuav txiav txim siab qhov ligand tshwj xeeb thiab cov cim qhia hauv lub cev. ECM cov teeb liab raug xa mus rau cov neurons los ntawm integrins, yog qhov tseem ceeb rau cov duab ntawm tes, ciaj sia taus, motility, proliferation, kev loj hlob, kev sib txuas ntawm neuronal, thiab synaptic plasticity [129]. Integrins kuj tseem ceeb heev rau cov teeb liab intracellular ntawm kev loj hlob yam tseem ceeb [130], uas yog cov paub zoo modulators ntawm neuronal ciaj sia taus los ntawm kev thaiv cov txheej txheem kev tuag. 1 integrin subunit yog qhov tseem ceeb rau kev sib cuam tshuam ntawm tes-ECM, thiab nws cov blockage txaus los ua rau anoikis [36] thiab neuronal apoptosis [131]. Tsis tas li ntawd, cov teeb liab intracellular ntawm lub subunit no muaj feem cuam tshuam rau kev ciaj sia ntawm cov hlwb hauv lub hlwb [132], thiab lawv qhov tsis xws luag muaj nyob rau hauv cov teeb meem neurodegenerative [133].

Txawm li cas los xij, cov hlwb tau tsim cov tshuaj tiv thaiv anoikis subroutines los tiv thaiv kev tuag, uas yog pib los ntawm tyrosine kinases, me GTPases [128], NF-kB [134], PI3K / AKT, proto-oncogene tyrosine-protein kinase (Src) lossis ERK axes. , thiab los ntawm autophagy [135,136]. NF-kB modulates anti-anoikis los ntawm qhov tshwm sim ntawm anti-apoptotic proteins xws li Bcl-2 thiab IAP- 1 [135], lub sijhawm PI3K / AKT lub luag haujlwm hauv cell survival yog dav sau tseg thiab pab txhawb rau kev ciaj sia. ntawm cov hlwb sib txawv [36,37]. ECM detachment kuj induces autophagy, uas yog ib tug self-tiv thaiv mechanism ua rau bypass apoptosis [135]. Cov ntaub ntawv pov thawj no qhia ntxiv txog kev sib txuas sib txuas ntawm kev tiv thaiv tus kheej.

Anoikis tseem muaj nyob rau hauv neuronal tuag tom qab TBI vim qhov nce ntawm matrix metalloproteinase (MMP) uas rhuav tshem ECM proteins [137]. MMPs qhia thiab qib tau hloov kho tom qab neurotrauma, thiab lawv muaj lub luag haujlwm sib txawv hauv axonal degeneration, glial scar formation, thiab synaptic remodeling. Hais txog kev muaj sia nyob neuronal, qhov inhibition ntawm MMP9 ua rau muaj kev tiv thaiv hauv cerebral ischemia los ntawm kev txo qis ntawm laminin degradation [38]. MMPs kuj tseem cuam tshuam rau hauv neurodegeneration [138]. Cov kev tshawb fawb tsis ntev los no tau piav qhia tias qhov inhibition ntawm MMP9 muaj kev tiv thaiv hauv lub cev muaj zog los ntawm ALS nas qauv [39,40] thiab hauv AD qauv [41]. Yog li ntawd, kev kho mob los tiv thaiv MMPs tshwj xeeb yuav tsis ncaj qha tswj kev tiv thaiv anoikis hauv cov neurons ua kom nws txoj sia nyob.

3.5. Cytoskeleton thiab Motor Transporters

Lub neuronal cytoskeleton yog tsim los ntawm peb qhov sib txawv ntawm cov txheej txheem: micro-tubules (MTs), nruab nrab filaments (IF), thiab actin microfilaments. Lawv muaj cov haujlwm sib txawv ntawm tes: MT tswj cov neurite thiab dendrite dynamics [139], actin yog tus saib xyuas ntawm cell morphology [140], thiab IF tsav txhua yam kev ruaj ntseg rau cytoskeleton qauv [141]. Cov teeb meem nyob rau hauv cov txheej txheem complexes raug pom nyob rau hauv cov kab mob neurodegenerative, nyob rau hauv peripheral neuropathies, nyob rau hauv synaptic dysfunction, thiab ua rau cov laus laus poob [141-146].

Lub zog ntawm MTs yog cov txheej txheem tswj tau zoo, thiab nws qhov kev tsis txaus ntseeg tuaj yeem ua rau muaj kev puas tsuaj loj rau cov neeg muaj sia nyob lossis kev ua haujlwm ntawm axon [142], thaum nws qhov kev ruaj khov thaiv kev tuag neuronal [147] thiab ua kom cov axonal loj hlob hauv nruab nrab paj hlwb [148]. Ntau yam ntxiv, cov qauv cytoskeletal yog cov kev tsheb ciav hlau, thaum lub kinesin thiab dynein motor proteins yog cov tsheb ciav hlau uas hloov cov khoom thauj los ntawm anterograde lossis retrograde thauj, feem. Yog li ntawd, lub cev muaj zog complexes kuj tseem ceeb rau kev ciaj sia ntawm neurons. Tsev neeg kinesin yog tsim los ntawm kinesin-1 (keeb kwm npe KIF5c) thiab kinesin-3 (KIF1A, KIF1B, thiab KIF1B ) cov tswv cuab [149]. KIF5c yog enriched hauv MNs [150], thiab nws cov caj ces ablation yog txuas nrog MN kab mob thiab tuag tes tuag taw [149,151]. Nws tau tsis ntev los no tau hais txog hauv pathogenesis ntawm ALS [152]. Qhov tsis zoo ntawm nws cov kev cuam tshuam nrog MTs ua rau axonal degeneration thiab tom qab neuronal tuag [153]. KIF5c cuam tshuam ua rau mitochondrial dynamics disorders, uas ua rau neuronal ciaj sia los yog tuag nyob ntawm qhov stimuli. Ntxiv mus, KIF5c finne-tunes mitochondrial muaj nuj nqi, hloov mus rau hauv cellular noj qab haus huv (saib hauv qab no, Tshooj 3.6.) [42], thiab nws cov kev hloov kho yuav txhawb nqa.neurotiv thaiv. Protein aggregates, xws li amyloid- , muaj kev cuam tshuam rau KIF5a stability, ua rau muaj kev cuam tshuam mitochondrial zog thiab ua haujlwm zoo [154].

Cov retrograde proteins kuj exertneurotiv thaiv. Lawv yog cov dyneins thiab yog multiprotein complexes tsim los ntawm cov proteins sib txawv, nrog rau p150glue (dynactin1 / DCNT1) yog cov subunits ntau tshaj. Lub dysfunctional dynactin subunit 1 (DCTN1) tau siv los ua tus qauv ALS nas, thiab nws qhov kev hloov pauv ua rau muaj kev thauj mus los tsis zoo uas ua rau ALS zoo li phenotype hauv nas [155,156]. Cov nas KO qhia txog hnub nyoog-raws li MN kev tuag, uas yog nrog los ntawm autophagy blockage [157]. DCTN1 muaj lub luag haujlwm meej hauv autophagic vacuoles thauj hauv lub cev neuronal, thiab nws qhov kev cuam tshuam ua rau amphisome tsub zuj zuj hauv cov axons distal, ua rau AD-zoo li phenotype [158]. Lub dynein adapter Rab-interacting lysosomal protein (RILP) plays lub luag haujlwm tseem ceeb hauv autophagosome biogenesis, thauj, thiab nws inhibition ua rau cov txheej txheem autophagic tsub zuj zuj [44]. Ua ke, nws tau raug pom tias MT tsis ua haujlwm, ua ke nrog kinesin thiab dynein aberrant localization, ua rau lysosomal ua haujlwm tsis zoo, uas ua rau autophagosome tsub zuj zuj thiab presynaptic dystrophy hauv AD [159]. Lub overexpression ntawm DCTN1 nyob rau hauv osteoclasts tiv thaiv apoptotic tuag, qhia hais tias lub cev muaj zog proteins kuj muaj lub luag hauj lwm nyob rau hauv zam cellular tuag nyob rau hauv lwm hom cell thiab cov ntaub so ntswg [43].

Hauv cov ntsiab lus, kev txo qis hauv axonal thauj yog tam sim no nyob rau hauv ntau cov kab mob neurodegenerative thiab tom qab lub paj hlwb raug mob. Qhov tsis xws luag yuav ua rau muaj kev hloov pauv hauv MT qauv thiab / lossis lub cev muaj zog molecular xav tau rau kev thauj mus los axonal [5]. Kev thauj mus los zoo axonal yog qhov tseem ceeb rau kev ua haujlwm ntawm cov neurons, thiab kev puas tsuaj hauv cov txheej txheem no ua rau muaj kev puas tsuaj rau neuronal. Txhawb nqa lub tshuab thauj khoom ntawm tes, los ntawm kev ruaj khov ntawm cytoskeleton lossis txhim kho lub cev muaj zog protein ntau / kev ua haujlwm, tau pom tias yog neuroprotective los ntawm kev rov tsim kom muaj qhov tseeb autophagy flux hauv cov neuron [5].

3.6. Mitochondrial Zoo-Function

Neurons 'kev ua haujlwm nyob ntawm lub zog thiab calcium (Ca2 ntxiv) sib npaug, yog li mitochondria kev ua tau zoo yog qhov tseem ceeb rau lawv. Mitochondria tsis yog static organelles. Lawv hloov cov duab, qhov loj me, tus lej, lossis qhov chaw nyob hauv lub xovtooj ntawm tes thiab muaj peev xwm fuse lossis faib los ntawm kev sib cais kom hloov mus rau qhov xav tau ntawm tes. Lawv tsim lub zog los ntawm lub voj voog tricarboxylic acid (TCA) thiab oxidative phosphorylation (OXPHOS) ntawm electron thauj saw (ETC). Kev ua kom OXPHOS yuav ua rau ROS, uas muaj ntau yam kev ua haujlwm (kev sib txawv, autophagy, kev tiv thaiv kab mob) ntawm qib physiological [160] thiab axonal regeneration [60]. Txawm li cas los xij, ntawm qib supra-physiological, ROS muaj teeb meem vim lawv ua rau muaj kev puas tsuaj rau lipids, DNA, thiab cov proteins. Cov kev hloov pauv no tau txuas nrog cov kab mob neurodegenerative, SCI, thiab TBI. Mitochondria kuj tseem ua tus tswj hwm tseem ceeb ntawm neuronal ciaj sia los ntawm lawv txoj kev koom tes hauv txoj hauv kev uas hloov pauv kev tuag neuronal.

Mitochondria yog thauj nyob ib ncig ntawm lub cell los ntawm cytoskeleton, lub cev muaj zog proteins, thiab cov adaptors tsim nyog. Hauv cov neurons, lawv feem ntau raug xa mus rau MTs los ntawm cov adapters Miro thiab Milton/trafficking kinesin-binding protein 1 (TRAK) proteins [161]. Cov mitochondria txav mus rau hauv cov neurons yog qhov tseem ceeb los tswj kev ua kom pom kev zoo hauv cov synapses, tsim lub zog, buffering Ca2 ntxiv, thiab lwm yam. [162]. Mitochondria feem ntau nyob ze rau ER, tsim mitochondria-associated ER membranes, los yog mitochondria-associated membranes (MAMs). Cov membrane microdomains yog thim rov qab tethers uas sib koom ua ke thiab cuam tshuam ntau yam ntawm cov txheej txheem ntawm tes, piv txwv li, kev sib txuas / thauj cov lipids, Ca2 ntxiv rau kev ua haujlwm / taw qhia, autophagy, mitochondrial zoo li qub thiab loj, apoptosis, thiab lub zog metabolism [163]. MAMs tau hloov pauv hauv cov kab mob neurological xws li AD, PD, thiab ALS [164]. Mitochondria ua raws li lub hub ntawm ATGs, muab cov membranes rau kev tsim autophagosomes, thiab modulating autophagic flux [165]. Mitochondria kuj raug kev txom nyem UPR (mt), thiab nyob ntawm txoj kev ua kom muaj zog, nws tau txuas nrog kev ua neej nyob ntev hauv cov cab thiab nas [166], tab sis nws cov overactivation ua rau neurodegeneration [167].

Mitochondrial dysfunction tshwm sim los ntawm tus naj npawb ntawm mitochondria tsis txaus, tsis muaj peev xwm muab cov substrates tsim nyog rau lawv, lossis ua haujlwm tsis zoo hauv lawv cov khoom siv hluav taws xob thiab ATP-synthesis machinery. Cov qib siab ntawm ROS thiab cov kab mob sib xws (RNS) tuaj yeem ua rau nruab nrab los ntawm dismutase enzymes thiab antioxidants [168]. Kev hloov pauv hauv cov enzymes no thiab qee qhov mitochondrial respiratory complexes tau pom nyob rau hauv cov kab mob neurodegenerative xws li ALS thiab PD [169]. Perturbations nyob rau hauv tus lej mitochondrial thiab ua haujlwm hnyav ua rau cellular homeostasis thiab ua rau qhov pib ntawm tus kab mob. Yog li ntawd, cov hlwb nrhiav kom muaj qhov sib npaug ntawm cov txheej txheem tawm tsam ntawm mitochondrial biogenesis thiab tshem tawm. Lub tsub zuj zuj ntawm dysfunctional mitochondria thiab / los yog poob ntawm nws biogenesis ua cell tuag. Cov kev kho mob tsis ntev los no los tiv thaiv neurodegeneration lub hom phiaj los txhawb mitochondrial biogenesis los ntawm modulating NAD ntxiv [170], epigenetic marks [171], lossis modulating serotonin axis hauv lub hlwb [172]. Tsis zoo mitochondrial clearance los ntawm mitophagy kuj yieldsneurotiv thaiv. Lub overexpression ntawm PTEN-induced kinase 1 (PINK1), uas yog qhov tseem ceeb rau kev pib cov txheej txheem mitophagy, nce neuronal ciaj sia nyob rau hauv ib tug yoov qauv ntawm HD [45]. Tsis tas li ntawd, NAD ntxiv ntxiv txo cov neurotoxicity hauv PINK1-mutant qauv ntawm PD [173].

Mitochondria muaj nuj nqi yog crosslinked nrog ROS thiab cellular antioxidant teb. Nyob rau hauv txoj kev ntawd, qhov kev hloov pauv ntawm Nuclear factor erythroid-derived factor 2-related factor 2 (Nrf2) regulates the expression of cytoprotective and detoxifying genes to combat oxidative stress and neuroinflammation, aiming to txo ​​neural damage. Yog li ntawd, nws tuaj yeem yog qhov kev siv tau zoo los ncua kev kis kab mob hauv cov kab mob neurodegenerative [174–176]. Raws li kev txhawb nqa ntawm ROS, Nrf2 dissociates los ntawm Kelch-zoo li ECH-koom nrog cov protein (Keap1), yog li tswj cov kev qhia ntawm antioxidant enzymes [177]. Nws tau raug piav qhia tias Keap1 kho kom haum rau ubiquitination ntawm p62 [178]. Thaum Keap1 yog downregulated, p62 yog sau nyob rau hauv hlwb thiab ua rau cytotoxicity, thaum nws overexpression txhawb lub degradation ntawm p62 ntawm txoj kev autophagy. Ntawm qhov tod tes, p62 qhib Nrf2 los ntawm txoj kev autophagy los tsim p62-Keap1-Nrf2-antioxidant responsive element (ARE) txoj hauv kev thiab tiv thaiv oxidative puas tsuaj los ntawm ROS [179 ]. Ntxiv mus, Nrf2 cov ntaub ntawv kev cai voj voog koom nrog cov kev cai ntawm mitochondrial biogenesis. Nrf2 nce qhov kev qhia ntawm peroxisome proliferator-activated receptor-gamma coactivator 1-alpha (PGC-1 ) thiab nuclear respiratory factor (NRF1), uas ncaj qha koom nrog kev cai ntawm mtDNA transcription. Thaum kawg, Nrf2 tswj kev qhia ntawm PINK1, uas ua lub luag haujlwm tseem ceeb hauv mitophagy induction [180], qhia tias lub peev xwm antioxidant ntawm tes kuj cuam tshuam rau mitochondria xeev.

Cov kab mob neurodegenerative muaj feem xyuam rau ob qho tib si inhibition ntawm Nrf2 txoj hauv kev thiab kev ua haujlwm tsis zoo ntawm autophagy, uas ua rau muaj kev sib txuam ntawm ROS, senescent organelles thiab misfolded proteins [181,182]. Cov kab mob neurodegenerative muaj feem xyuam rau ntau cov protein sib sau ua ke thiab ROS, ua rau p62-Keap1-Nrf2 cov lus pom zoo, uas yog cov txheej txheem tiv thaiv hauv neurons [183,184]. Nrf2 qhia yog tsawg hauv AD tsiaj qauv thiab AD neeg mob hlwb [185]. Nrf2 binding rau ARE tshwm sim sai sai thaum lub sij hawm kis kab mob, uas cuam tshuam nrog kev nce hauv ROS ntau lawm [186]. Nrf2 neuroprotectants los ntawm kev txo qis ROS tiam thiab A -mediated ROS-induced toxicity [187,188]. Hauv HD, muaj qhov tsis ua haujlwm ntawm mitochondrial complex II, ua rau muaj kev nce hauv ROS [48]. Hauv thawj theem ntawm HD, kev kho mob nrog Nrf2 agonist ua rau muaj kev nce ntxiv ntawm cytoprotective genes ntawm Keap1-Nrf2-ARE hauv astrocytes thiab microglia [189]. Kev ua haujlwm ntawm Keap1-Nrf2-ARE txoj hauv kev los ntawm cov molecules me hauv astrocytes accelerates qhov tsis kam ntawm cov neurons rau cov tsis-excitotoxic glutamate toxicity [46-48]. Hloov mitochondria muaj nuj nqi, biogenesis, thiab mitophagy yog cov yam ntxwv tseem ceeb hauv PD, thiab Nrf2 yog qhov tseem ceeb ntawm kev hloov pauv uas tswj hwm mitochondrial zoo tswj thiab homeostasis [190]. Hauv PD, muaj kev ua haujlwm ntawm Nrf2-ARE system [191,192] thiab nws cov tshuaj siv tshuaj tiv thaiv PD kev nce qib [49,50]. Nrf2 activation plays lub luag haujlwm tiv thaiv ROS thiab cell tuag los ntawm superoxide dismutase 1 (SOD1) mutant protein. Tsis tas li ntawd, astrocyte Nrf2 overexpression ua rau kom muaj sia nyob ntawm SC MNs thiab txuas ntxiv txoj sia nyob hauv SOD1 transgenic nas [51,52]. Tsis tas li ntawd, kev sib tham ntawm p62 thiab Keap1-Nrf2 txoj hauv kev hauv cov ntsiab lus ntawm autophagy tuaj yeem ua lub luag haujlwm tseem ceeb hauv kev tshem tawm ROS, tiv thaiv oxidative puas tsuaj, thiab hloov kho ER kev ntxhov siab thaum lub sij hawm cerebral ischemia-reperfusion raug mob [53].

Thaum kawg, mitochondria tsav cov neeg muaj sia nyob, vim tias lawv paub qhov pib tuag sab hauv thiab sab nraud, ua rau muaj kev cuam tshuam ntawm cov mitochondria thiab tom qab ntawd rov ua dua rau ib lossis ntau txoj kev tuag ntawm tes uas ua rau muaj ntau hom kev tuag ntawm tes (xws li intrinsic apoptosis. Ib.) [193].

cistanche cog hauv AD

4. Targeting Systemic Modulation

4.1. Caloric txwv

Caloric restriction (CR) ncua kev ua neej nyob hauv cov kab mob sib txawv thiab muaj kev tiv thaiv rau ntau lub cev. CR cuam tshuam rau tag nrho cov kab mob: los ntawm cov kab mob hauv lub cev mus rau cov neeg sib txawv subcellular. Hauv xyoo 2010, Kromer thiab cov neeg koom tes tau qhia tias CR cov txiaj ntsig yog nyob ntawm SIRT1-dependent autophagy [194]. Ntawm qhov tod tes, nws tau taw qhia tias CR yog neuroprotective hauv PD tus kab mob los ntawm Ghrelin-AMPK axis, nrog AMPK yog ib qho tseem ceeb inducer ntawm autophagy [195]. Muab qhov pom tseeb tsis muaj peev xwm tswj tau CR mus sij hawm ntev, kev kho mob tau txais txiaj ntsig los nrhiav cov tshiab CR "mimetics" (CRM), uas ua rau cov teebmeem ntawm lub cev ntawm CR hauv lub cev [196]. Ob leeg CR thiab CR-mimetics tau soj ntsuam kev ua tau zoo hauv AD nas qauv los ntawm kev txhim kho kev paub txog kev ua haujlwm los ntawm kev siv autophagy induction [197], yog li lawv yog cov kev kho tshiab rau kev kho mob neurodegeneration.

4.2. Kev tawm dag zog

Kev tawm dag zog lub cev tau txais kev txaus siab vim nws lub peev xwm los txo cov kab mob pathophysiological xws li mob neuropathic lossis txhim kho cov txiaj ntsig ua haujlwm hauv cov qauv mob stroke [198]. Nws kuj tseem ua rau qeeb ntawm PD kev loj hlob los ntawm inhibition ntawm cov tshuaj tiv thaiv kab mob thiab kev txhim kho ntawm cov tshuaj tiv thaiv antioxidant [199]. Nws tau piav qhia tias kev tawm dag zog ua haujlwm los ntawm kev nce qib endogenous ntawm neurotrophic yam [200,201]. Ntxiv mus, nws modulates cov leeg nqaij hormone secretion, txhawb kev tiv thaiv los ntawm lub hlwb, neurogenesis, thiab ameliorating hlwb laus [202]. Qhov tseeb, tsis ntev los no tau piav qhia tias tib yam tshuaj hormones, irisin, muaj lub luag haujlwm hauv kev tsim cov pob txha [203], qhia tias kev tawm dag zog cuam tshuam rau tag nrho lub cev.

5. Nrhiav Neuroprotectant zoo: Dab tsi muaj thiab qhov twg peb mus

Cov cim tseem ceeb ntawm cov kab mob neurodegenerative yog ib qho kev ua kom tsis raug ntawm UPR, tsub zuj zuj ntawm cov txheej txheem autophagic, mitochondrial kev ua haujlwm tsis zoo, thiab lwm yam. Nyob rau hauv tas li ntawd, lawv yuav overwhelm neurons, provoking lawv demise. Ib qho zoo neuroprotectant yuav tsum kho cov txheej txheem no los ntawm kev txhawb nqa lub cell nrog kev ua kom tiav rau kev laus / kev thuam. Peb yuav tsum tau hloov kho tag nrho cov molecular network nyob rau hauv lub xov tooj ntawm tes, thawb nws mus rau ib tug ua tiav restoration ntawm functions. Cov tshuaj pom zoo xws li Riluzole rau ALS [204], lossis kev sim tshuaj mus ntxiv, xws li Rapamycin rau ALS [204], Spermidine, thiab DH rau AD [205,206], tsuas yog tsom ib qho ntawm cov txheej txheem degenerative, thiab cov neuron tau dhau los ntawm lwm tus. Txawm hais tias lawv tuaj yeem ua rau muaj txiaj ntsig zoo, peb xav kom nrhiav cov noob caj noob ces lossis tshuaj kho mob kom pom zoo rau txoj hauv kev sib txawv molecular - kev kho ntau hom phiaj - tsis yog ib lub hom phiaj xwb.

Kev nthuav qhia tshwj xeeb ntawm qee cov proteins xws li SIRT1, BIP, thiab / lossis ATG5 pab txhawb kev muaj sia nyob ntawm lub paj hlwb tom qab raug mob thiabneurotiv thaivhauv cov kab mob neurodegenerative. Lawv feem ntau yog kho UPR lossis autophagy tes hauj lwm. Kev ua kom SIRT1 los ntawm kev siv cov nas transgenic lossis cov kab mob kis tau pom muaj kev tiv thaiv hauv cov kab mob neurodegenerative sib txawv xws li ALS, AD, thiab HD [207-209] thiab tom qab raug mob paj hlwb [55]. SIRT1 deacetylase kev ua ub no pom zoo sib txawv endogenous mechanisms ntawm kev tiv thaiv: autophagy, modulates UPR los ntawm attenuating PERK, thiab tsub kom ATF6 cleavage [23,210], muaj anti-apoptotic teebmeem, thiab modulates AKT kev ua rau inhibit anoikis [211,212]. Yog li ntawd, qhov kev hloov pauv meej ntawm nws tuaj yeem txhim kho cellular resilience. Los ntawm peb txoj kev tshawb fawb tsis ntev los no, peb xaus lus tias kev hloov pauv SIRT1 deacetylase kev ua haujlwm yog ib qho tseem ceeb ntawm lub network molecular kom ua tiav cellular resilience [54,55]. Thaum kawg, BIP overexpression tiv thaiv cov aggregates thiab induces autophagy thiab mitophagy [99], yog li nws cov kev hloov kho kuj yog ib txoj hauv kev zoo rau pawg sib txawv neuroprotective txoj hauv kev.

6. Cov lus xaus

Boosting endogenous mechanisms ntawmneurotiv thaivqhib cov kev kho mob zoo siab los kho cov kab mob neurodegenerative lossis tswj cov ntaub so ntswg homeostasis tom qab neuro-trauma. Txawm hais tias qhov no yog qhov tsis tau tshawb nrhiav tam sim no, nws tuaj yeem txhawb nqa cov txiaj ntsig biomedical zoo dua li thaiv cov cim qhia ntawm cov kab mob physiological. Yog li, kev pom zoo rau lawv los ntawm kev tshuaj ntsuam genetic, pharmacological, los yog cov kev kho mob-modulation tuaj yeem ncua kev loj hlob ntawm pathology thiab txhim kho kev ua haujlwm zoo. Txoj kev kho kom zoo tshaj plaws yuav tsum koom nrog kev hloov pauv ntawm cov txheej txheem endogenous ntawm kev tiv thaiv kom rov ua qauv ua tiav kev sib txuas thiab ua tiav kev tiv thaiv.

Tus sau kev koom tes: DR-G. thiab SM-M.-A. sau cov ntawv sau thiab CC ua qhov kev tshuaj xyuas tseem ceeb. 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 tsis tau txais nyiaj txiag sab nraud.

Daim Ntawv Qhia Txog Cov Ntaub Ntawv: Tsis muaj cov ntaub ntawv tshiab raug tsim lossis tshuaj xyuas hauv qhov kev tshawb fawb no. Kev sib faib cov ntaub ntawv tsis muaj feem xyuam rau kab lus no.

Kev tsis sib haum xeeb ntawm kev txaus siab: Cov neeg sau ntawv tshaj tawm tsis muaj kev cuam tshuam ntawm kev txaus siab.