Prion Protein: Cov Molecule Ntawm Ntau Daim Ntawv Thiab Lub ntsej muag Part 2

5. Prion Protein thiab Ischemic Strokes

Hauv ntu dhau los, peb tau pom tias cov tsiaj txhu muaj kev nyuaj siab ntau dua tooxidative stress. Cov kev tshawb fawb txhawb nqa lub tswv yim tias PrPC ua cov tshuaj tiv thaiv antioxidant los ntawm kev tswj glutathione reductase kev ua haujlwm [117,118] thiab los ntawm kev tswj hwm superoxide dismutase (SOD) los ntawm ion binding [119–123].

Oxidative stress yog ib qho tshwm sim uas lub cev tsim tawm ntau dhau dawb radicals thiab lwm yam active oxidants nyob rau hauv lub cev thiab pathological mob, uas tshaj lub peev xwm clearance, yog li ua rau puas hlwb thiab cov ntaub so ntswg. Ntau cov kev tshawb fawb tau pom tias oxidative kev nyuaj siab yog ze rau ntau yam kab mob xws li Alzheimer's kab mob, Parkinson's disease, Alzheimer's disease, thiab lwm yam.

Txawm li cas los xij, kev tshawb fawb tsis ntev los no tau taw qhia tias qhov nruab nrab ntawm oxidative kev nyuaj siab tuaj yeem pab txhim kho kev nco. Qee cov kws tshawb fawb ntseeg tias qhov nruab nrab ntawm oxidative kev nyuaj siab tuaj yeem txhawb cov neurons los tsim cov antioxidants ntau dua, yog li txhim kho lawv lub peev xwm los tiv thaiv oxidative kev nyuaj siab, tiv thaiv cov neurons los ntawm kev cuam tshuam los ntawm cov teeb meem yuam kev, thiab yog li txhim kho kev kawm thiab kev nco.

Tsis tas li ntawd, cov kev tshawb fawb tau pom tias qhov nruab nrab ntawm oxidative kev nyuaj siab kuj tuaj yeem txhawb kev tsim thiab ntxiv dag zog ntawm synapses, uas kuj yog qhov tseem ceeb hauv kev nco. Cov kws tshawb fawb tau pom tias qee qhov txiaj ntsig oxidative kev ntxhov siab molecules tuaj yeem txhawb kev tsim cov synapses thiab txhawb kev ntxiv dag zog ntawm synapses, yog li txhim kho kev kawm thiab kev nco ua haujlwm.

Yog li ntawd, txhawm rau txhim kho kev nco, peb yuav tsum tsis txhob tawm tsam oxidative kev nyuaj siab ntau dhau. Qhov nruab nrab ntawm oxidative kev nyuaj siab yog qhov zoo rau tib neeg lub cev, thiab nws tuaj yeem txhawb nqa thiab ua haujlwm nrog kev tawm dag zog thiab noj zaub mov nplua nuj hauv antioxidants. Nyob rau tib lub sijhawm, peb kuj yuav tsum tau ua tib zoo saib xyuas cov qib ntawm oxidative kev nyuaj siab thiab xyuas kom meej tias nws nyob rau hauv ib nrab kom tau txais kev noj qab haus huv zoo tshaj plaws thiab kev nco zoo. Nws tuaj yeem pom tias peb yuav tsum txhim kho kev nco, thiab Cistanche tuaj yeem txhim kho kev nco zoo vim Cistanche 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

PrP-knockout nas tau pom tias txo kev tiv thaivROS thaum cov nas uas muaj kab mob prion tau pom tias muaj kev ntxhov siab oxidative ntau ntxiv, feem ntau yog qhov tshwm sim ntawm PrPC poob haujlwm [124–126].

Nyob rau hauv oxidative kev nyuaj siab, PrP mRNA qib nce, uas txhais tau hais tias oxidative kev nyuaj siab upregulates PrPC qhia [127]. Ischemic stroke yog ib qho mob uas poob ntawm cov ntshav ntws hauv lub hlwb hauv cheeb tsam ua rau cov mob hypoxic thiab lub hlwb puas [128].

PrP-knockout tsiaj cov qauv raug toischemia tau pom muaj kev puas tsuaj rau ischemic thiab txo txoj hauv kev rov tsim dua tshiab whereasthe muaj peev xwm ntawm PrPC synthesis ua rau PrPC overexpression thiab txo ischemicdamage [127].

Kev tshawb fawb ntawm ischemic strokes tau qhia tias PrPC overexpression tuaj yeem txo qhov mob me me piv nrog cov nas qus, hais txog PrPC rau lub luag haujlwm tiv thaiv kev puas tsuaj inischemia [129–135].

Tom qab kev thuam ntawm ischemic, PrPC cuam tshuam nrog cov txheej txheem neuroprotective thiab rov tsim dua tshiab los ntawm kev cuam tshuam nrog ntau yam cytosolic thiab transmembranesignal proteins.

Ntawm lwm tus, PrPC tau cuam tshuam nrog kev txhim kho ntawm extracellular signal-regulated kinase (ERK1/2) [133,136,137], ua kom cov phosphatidylinositol3-kinase/protein kinase B/Akt (PI3K/Akt) txoj kev [138– 142], kev hloov pauv ntawm N-methylD-aspartate (NMDA) receptor-mediated toxicity [143], ua kom cov cAMP-dependentprotein kinase A (PKA) txoj kev [144–146] thiab kev cuam tshuam nrog kev ntxhov siab-inducible protein 1(STI1) [ 146], tag nrho cov ua rau muaj sia nyob neuron, neurite outgrowth thiab neuroprotection.

PrPC yog ib tug receptor ntawm Fyn kinase, ib tug tswv cuab ntawm Src tsev neeg ntawm tyrosine kinases (SFKs) [146]. Los ntawm Fyn kinase activation, PrPC mediates oligomer-induced toxicity inneurodegenerative kab mob [147–150] thiab txhawb nqa neurite outgrowth los ntawm phosphorylation ntawm GluN2A domain ntawm neuronal cell adhesion molecule (NCAM) [151].

Fyn kinase thiab lwm tus tswv cuab ntawm tsev neeg SFK koom nrog kev puas tsuaj rau ischemic [152–155].Qhov inhibition ntawm SFKs nyob rau hauv lub ntiaj teb no ischemia qauv thiab inhibition ntawm Fyn-mediatedphosphorylation ntawm GluN2A nyob rau hauv ib tug qauv ntawm neonatal HII ua rau muaj zog neuronalsurvival [ 156–158] whereas lub overexpression ntawm Fyn nyob rau hauv tus qauv ntawm neonatal HII ua rau increased hlwb puas [159].

Qhov inhibition ntawm SFKs nyob rau hauv tus nas qauv ntawm ischemia kuj ua rau txo qis ischemic ntim thiab txhim kho cerebral muaj nuj nqi tom qab provocation [155].

Raws li cov nyhuv no tsis tau pom nyob rau hauv cov nas Fyn-knockout, peb xav tias ligands lwm yam tshaj li Fyn kinase kuj yuav cuam tshuam rau ischemia insult recovery [155].PrPC fragments kuj tau pom tias muaj kev koom tes hauv ischemic stroke.

Fragments N1 thiab N2 tau pom tias ua haujlwm tiv thaiv hauv cellular stress [160–162] thiab modulate quiescence ntawm neural qia hlwb hauv cov neeg laus neurogenesis thaum mob stroke [163] whereas PrPC fragmentsC1 thiab C2 tau koom nrog hauv kev tswj p53-dependent apoptosis thiab cell survival [164] .Fragment C1 tau pom tias muaj kev nplua nuj nyob hauv cov EVs me me (EVs) qhov uas nws tau ua zoo ib yam li toviral nto proteins [165,166].

Vim li no, nws tuaj yeem cuam tshuam rau cov ntaub ntawv sib txuas ntawm intercellular ntawm sEVs thiab lawv lub hom phiaj lub hlwb thiab pab txhawb rau lawv cov uptake [63].Brenna li al. tau kawm txog qhov sib xws ntawm cov cellular uptake ntawm lub hlwb-derived sEVs los ntawm PrP-knockout nas thiab cov nas qus tom qab mob stroke [128].

Lawv tau pom tias sEVslacking PrP tau nce nrawm dua nrog kev ua haujlwm zoo dua thiab tau yooj yim txheeb rau hauv lysosomes dua li sEVs uas muaj PrP thiab fragment C1 [128].

FragmentN1 kuj tau pom tias muaj kev koom tes hauv kev tswj hwm kev sib cuam tshuam ntawm microglia thiab lwm lub hlwb hlwb. Kev tshawb fawb hauv vitro tsis ntev los no ntawm kev sib xyaw ntawm cov kab mob neuronal thiab microglia coculture tau pom tias tawg N1 txhawb kev hloov pauv hauv cell morphology thiab metabolism thiab induced Cxcl10 secretion [167].

Tsis tas li ntawd, fragment N1 tau pom tias muaj kev cuam tshuam microglia los hloov cov membrane muaj pes tsawg leeg rau ntau dua GM1 cov ntsiab lus ntawm qhov chaw sib cuam tshuam nrog cov hlwb nyob ib puag ncig hauv kev sib koom ua ke tsis tau tsuas yog raws li kev sib txuas ncaj qha ntawm tes-rau-cell [167].

Fragment N1 kuj tau npaj los tiv thaiv cov neurons tiv thaiv staurosporine-induced Caspase-3 ua kom muaj nyob rau hauv tus qauv ischemic ntawm nas retina [60]. Cov txiaj ntsig no tau txais kev txhawb nqa los ntawm kev tshawb fawb hauv vitro uas qhov kev qhia ntawm PrPC tau tiv thaiv staurosporine lossis anisomycin-induced apoptosis [144,146]. Fragment N1 kuj tseem cuam tshuam txog kev tiv thaiv neuroprotection hauv cov kab mob neurodegenerative, uas tau tham txog ntau yam ntxiv hauv ntu tom ntej.

Nyob rau hauv lub xub ntiag ntawm anchored PrPC, recombinant PrP (recPrP) tuaj yeem induceERK1/2 thiab Akt signaling ntawm mesenchymal qia hlwb uas tuaj yeem pab txhawb kev sib txawv ntawm cov neuronal [168], txhawb nqa neurite outgrowth thiab pab txhawb kev loj hlob ntawm lub khob hliav qab [169].

Tsis ntev los no, nws tau tshaj tawm tias recPrP txhawb nqa neurite outgrowth thiab Schwann cell migration los ntawm ERK1/2 txoj kev [170].

Kev ua kom muaj feem cuam tshuam nrog NMDA receptors, low-density lipoprotein receptor-related protein-1 (LRP1), SFKs, thiab Trk receptors; nws zoo li yuav tsum tau ua qhov chaw ntawm nws tus kheej ntawm kev thauj mus los PrPC [170].

Hauv cov txheej txheem no, SFKs tau ua lub luag haujlwm tseem ceeb hauv recPrP-pib xov tooj ntawm tes taw qhia los ntawm kev ua kom Trk receptors, uas yog nce ntawm ERK1/2 [170,171]. Txawm hais tias recPrP tsis muaj glycosylation, nws yuav raug suav hais tias yog qhov tsim nyog ntawm kev tso tawm PrP.

Prion protein thiab prion protein fragments yog txuas nrog intercellular kev sib txuas lus thiab teeb liab, oxidative kev nyuaj siab, thiab neuroprotection thiab nthuav tawm lub hom phiaj txaus nyiam rau kev kho mob thiab kev tswj hwm ntawm cov txheej txheem no. Txawm li cas los xij, cov kev tshawb fawb ntxiv yuav tsum tau ua kom paub meej tias qhov cuam tshuam ntawm cov molecules hauv cov txheej txheem hais.

6. Prion Protein thiab Neurodegeneration

Neurodegeneration yog qhov kev poob qis ntawm cov qauv lossis kev ua haujlwm ntawm cov neurons, uas tuaj yeem cuam tshuam txog kev tuag ntawm tes. Nyob rau theem molecular, neurodegeneration yog txuas mus rau tsub zuj zuj ntawm misfolded proteins.

Kev sib sau ntawm cov protein aggregates ua rau mitochondria tsis ua haujlwm, ua rau oxidative kev nyuaj siab, thiab thaum kawg ua rau mob chronicinflammation. Neurodegeneration tshwm sim hauv cov kab mob xws li kab mob prion, PD, thiab ADdue rau kev sib sau ntawm PrPSc [26,172,173], -syn [174–177], thiab A isoforms [178,179], thiab tau protein [180–183], raws li.

Prion protein los yog prion protein fragments tau pom muaj kev cuam tshuam nrog cov neeg sawv cev sib txawv hauv cov kab mob neurodegenerative sib txawv tab sis lawv lub luag haujlwm yog nyob ntawm qhov kev kawm [24,81,184,185].

Nws tau raug tshaj tawm tias PrPC khi ntau yam ntawm -sheet-nplua nuj oligomers txuam nrog cov kab mob neurodegenerative [148–150].

PrPC koom nrog metabotropic glutamate receptor5 (mGluR5) thiab kho oligomer-induced toxicity los ntawm Fyn kinase [175,186–188].

Activated Fyn kinase tuaj yeem phosphorylate GluN2A thiab GluN2B subunits ntawm NMDAreceptors, uas tom qab ntawd hyperactivated thiab ua rau calcium influx thiab cell tuag [20,189].

Nws kuj tau pom tias PrPC tuaj yeem qhib Fyn kinase-mediated A oligomer toxicity los ntawm kev cuam tshuam nrog LRP1 [190]. Ib txoj kev tshawb fawb tsis ntev los no hauv daim teb no tau qhia tias, sib nrug ntawm LRP1, cov txheej txheem no suav nrog kev ua haujlwm ntawm 2-macroglobulin thiab cov ntaub so ntswg-hom plasminogen activator [191].

Cov kev tshawb fawb pom tau hais tias kev khi ntawm cov protein sib xyaw ua ke thiab PrPCcauses neurotoxicity thiab inhibits lub sij hawm ntev potentiation (LTP) [30,192]. Cov kev tshawb fawb tawm tsam kuj tau tshaj tawm tias tsis muaj qhov cuam tshuam tseem ceeb ntawm PrPC qib ntawm A -inducedLTP hauv PrP-knockout nas [193], cell ablation, lossis PrP overexpression [194].

Cov laj thawj ntawm qhov tsis sib xws tsis paub meej tab sis lawv tuaj yeem yog vim kev siv cov qauv sib txawv thiab hom tshuaj lom lossis tsis muaj tshuaj lom [195].A oligomers khi rau PrPC ntawm ob qhov chaw sib khi hauv qhov hloov pauv N-terminal ntawm PrPC, ntawm cov amino acid residues 23– 27 thiab 92–110 [192,195,196]. Sib nrug los ntawm A oligomers, PrPC tau tshaj tawm tias yog ib qho receptor rau -syn oligomers thiab tau aggregates.

Zoo ib yam li A oligomers, anchored PrPC khi me me soluble aggregates los yog luv luv fibrils ntawm -syn oligomers los yog tau aggregates nyob rau hauv lub saj zawg zog N-terminal ib feem [30,175,185,197–199].PrPC kuj tau pom tias uptake recombinant. -syn fibrils.

Ib qho qauv uas tsis muaj PrPC pom qhov txo qis ntawm -syn thiab -syn fibrils nyob rau hauv kev sib piv nrog cov tswj [177,185,197], ua rau tsawg-syn aggregation, astroglial activation, thiab poob ntawm dopaminergic neurons nyob rau hauv lub hlwb ntawm PrP-knockout nas [185].

Tsis tas li ntawd, PrP-knockoutmice tsis pom -syn-induced LTP impairment whereas kev kho mob nrog anti-PrPantibody tiv thaiv -syn-induced LTP tsis xws luag nyob rau hauv ib tug qauv ntawm PD [175]. Txawm hais tias cov kev tshawb fawb hais txog kev txhawb nqa PrPC thiab -syn oligomer interplay, La Vitola li al. pom tiasPrPC tsis yog yuav tsum tau rau kev kho kom haum xeeb ntawm -syn oligomer detrimental teebmeem hauv vitroor hauv vivo [33].

Txawm hais tias qhov sib txawv tsis tuaj yeem piav qhia hauv txoj kev tshawb fawb, nws kuj tseem tuaj yeem tshwm sim vim yog siv cov txheej txheem sib txawv ntawm cov txheej txheem sib xyaw ua ke lossis kev siv cov qauv sib txawv.

Anchored PrPC kuj tau pom tias khi tau sib sau ua ke thiab zoo li pab txhawb lawv qhov kev txhawb nqa [30,198,200]. Qhov tsis muaj PrPC los yog pretreatment nrog antiPrP thaiv cov tshuaj tiv thaiv tau pom tias yuav txo qis qhov nce ntawm recombinant tau aggregates thiab tshem tawm tau aggregate-induced toxicity [30,198,200].

Kev tshawb fawb txog kev sib xyaw ua ke PrP fragment N1 hauv cov kab mob neurodegenerative tau pom tias cov molecules tuaj yeem khi cov tshuaj lom A oligomers ntawm thaj tsam ntawm cov amino acidresidues 23-31 thiab 95-105.

Fragment N1 neutralizes tshuaj lom A oligomers los ntawm seizing lawv lub extracellular qhov chaw thiab txo oligomer-induced toxicity [61,195,201–204]. Cov kev tiv thaiv ntawm fragment N1 kuj tau pom nyob rau hauv vivo nyob rau hauv cov nas raug mob acuteA -induced toxicity [203]. Beland thiab cov neeg ua hauj lwm tau pom qhov nce hauv -cleavageof PrPC hauv lub hlwb ntawm cov neeg mob AD [205].

Raws li N1 feem ntau khi A oligomers, tej zaum nws yuav qhia tau hais tias qhov cleavage ua tiv thaiv kev loj hlob ntawm cov kab mob [205] whereas lub inhibition ntawm N1 ntau lawm txhawb AD kev loj hlob [42].

PrP shedding txo cov theem ntawm cell-anchored PrPC [78]. Qhov no ua rau txo qis ntawm cov substrate rau prion replication thiab txo qis ntawm cov receptor rau toxicoligomers [85,206].

Zoo ib yam li fragment N1, shed PrP kuj ntseeg tau tias yog kev tiv thaiv kab mob prion thiab lwm yam kab mob neurodegenerative [40,79,81]. Raws li tau hais hauv ntu dhau los, recPrP zoo ib yam li tso PrP.

Txawm hais tias nws tsis muaj glycans, daim ntawv qhia yuav siv tau los ua tus qauv los kwv yees lub luag haujlwm ntawm PrP hauv cov kab mob. RecPrP tau pom los ua kom muaj kev loj hlob ntawm cov synapses thiab neurite outgrowth nyob rau hauv lub xub ntiag ntawm anchored PrPC [170,207].

Zoo ib yam li fragment N1, recPrP kuj inhibited A oligomer tsim thiab neutralized A oligomer toxicity hauv AD qauv [203]. Cov kev tshawb fawb hauv vitro siv recPrP thiab nws cov txiaj ntsig tau qhia tias ob qho tib si N-terminal thiab C-terminal domains ntawm PrP yuav tsum tau ua kom muaj zog inhibition ntawm A fibril elongation [202,208] thiab txhawb kev tiv thaiv lub luag haujlwm ntawm kev tso tawm PrP hauv kev cuam tshuam ntawm A fibril tsim.

RecPrP kuj tau pom tias khi tau cov aggregates thiab -synoligomers thiab tuaj yeem ua rau lawv cov toxicity [30]. Txawm hais tias PrPC shedding ua kev tiv thaiv, txhim kho PrPC shedding tuaj yeem ua rau muaj kev tsis zoo ntawm cov kab mob lom xws li mob hauv CNS [83,209]. Jarosz-Griffiths et al. [82] tsis ntev los no tau tshaj tawm txog kev tiv thaiv lub luag haujlwm ntawm PrPshedding.

Cov kws sau ntawv tau tshaj tawm tias siRNA-mediated ADAM10 knockdown txo PrPCshedding thiab nce A oligomer binding whereas acitretin txhawb nqa PrPC shedding thiab txo qis A oligomer khi hauv cov hlwb neuroblastoma thiab hauv tib neeg-inducedpluripotent qia hlwb [82].

Nyob rau hauv ib daim ntawv tsis ntev los no los ntawm Linsenmeier li al., cov kws tshawb fawb tau soj ntsuam lub luag haujlwm ntawm kev tso cov qauv PrP tsis txawv txav [81]. Siv cov tshuaj tiv thaiv polyclonal sPrPG228 uas tshwj xeeb lees paubmurine PrP xaus nrog G228 [210] lawv tau pom tias hauv cov nas muaj kab mob prion, tso PrPcolocalized nrog PrPSc hauv amyloid plaques. Zoo ib yam li tus qauv ntawm tus kab mob prion, tso PrPwas kuj tau faib rau A deposits nyob rau hauv lub hlwb ntawm 5xFAD nas qhov twg nws tau pom boundto A oligomers thiab pom nyob rau hauv nruab nrab ntawm ntau amyloid plaques.

Vim qhov kev paub hauv daim teb no txog tam sim no, cov kws sau ntawv tau npaj siab tias lub cev muaj zog PrP tuaj yeem tiv thaiv cov kab mob prion thiab AD los ntawm kev thaiv cov tshuaj lom oligomers thiab / lossis los ntawm precipitating lawv intoless toxic deposits [81,211].

RecPrP thiab N1 kuj tseem tuaj yeem cuam tshuam A oligomerization, neutralize cytotoxicity ntawm preexisting A oligomers, tiv thaiv kev khi ntawm oligomers nrog lub xov tooj ntawm tes PrPC, thiab cawm A-induced impairment ntawm LTP [212].

Raws li recPrP thiab N1 ob qho tib si muaj kev sib koom ua ke ntawm cov protein oligomers, ob qho tib si molecules tau tshaj tawm los kuj khi -syn oligomersas nrog rau kev sib koom ua ke ntawm -syn oligomers thiab AD-associated amyloid- oligomers [199].

PrPC yog enriched nyob rau hauv extracellular vesicles (EVs) [128,213,214]. Tsis paub me ntsis txog kev ua haujlwm ntawm lub cev ntawm PrPC hauv EVs. Ntau qhov kev tshawb fawb tau qhia tias PrPC inEVs tiv thaiv cov hlwb tiv thaiv A toxicity [214–217].

Cov txheej txheem tom qab qhov nruab nrab ntawm cov tshuaj lom A oligomers los ntawm EVs tsis paub; txawm li cas los xij, nws tau xav tias nws zoo ib yam li recPrP lossis N1- txheej txheem kho kom haum.

Nws tau raug pom zoo tias exosomal PrPC ntes A oligomers ntawm thaj av N-terminal PrP (amino acid residues 23–31 thiab 95–105) [203], neutralizes oligomers, txhawb kev tsim ntawm A fibrils thiab upregulates internalization thiab degradation ntawm aggregates. los ntawm microglia [214–217].

Raws li recPrP thiab anchored PrPChave tau pom tias khi tau thiab -syn oligomers [30], exosomal PrPs yuav tsum ua tib yam. Los ntawm kev khi dawb toxic tau lossis -syn oligomers nyob rau hauv qhov chaw extracellular, exosomal PrPs tiv thaiv cov tshuaj lom oligomer khi rau anchored PrPC thiab inhibit toxic signaling hauv CNS ntawm cov neeg mob cov kab mob.

Exosomes txuam nrog PrPSc yog kis tau thiab ua rau muaj kev phom sij ntawm kev kis tus kab mob prion [218-222]. Txawm hais tias tseem tsis tau muaj kev tshawb fawb ncaj qha, exosomal PrPC kuj tseem tuaj yeem ua rau mob CNS. Kev ua haujlwm ntxiv yuav tsum tau ua los tshuaj xyuas lwm yam kev ua haujlwm lom neeg uas exosomal PrPC yuav muaj.

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