Prion Protein: Cov Molecule Ntawm Ntau Daim Ntawv Thiab Cov Ntsej Muag Part 1

Paub meej: Cellular prion protein (PrPC) yog ib qho glycosylphosphatidylinositol (GPI)-anchored protein feem ntau pom nyob rau hauv daim nyias nyias ntawm cov neurons. Vim muaj cov yam ntxwv ntawm cov qauv (qhov hloov tau yooj yim tailand structured core), PrPC cuam tshuam nrog ntau tus neeg koom tes.

Nyob rau hauv xyoo tas los no, ntau cov kev tshawb fawb tau pom tias cellular prion proteins muaj kev sib raug zoo nrog kev loj hlob thiab kev tu tsiaj nco.

Cellular prion (Herpes simplex virus, HSV) yog ib yam kab mob uas muaj nyob rau hauv tib neeg cov pej xeem thiab suav hais tias yog ib qho ntawm cov kab mob tseem ceeb tshaj plaws ntawm cov kab mob neurological thiab kab mob ntawm daim tawv nqaij. HSV-1 thiab HSV-2 yog ob hom kab mob uas tshwm sim hauv tib neeg.

Ib txoj kev tshawb fawb tsis ntev los no tau pom tias HSV-1 cov kab mob kis tau zoo tuaj yeem txhawb kev txhim kho thiab kev saib xyuas kev nco hauv tib neeg thiab tsiaj txhu. Cov txiaj ntsig ntawm txoj kev tshawb fawb no tau pom tias HSV-1 kab mob feem ntau tshwm sim nyob rau theem pib ntawm tib neeg lub neej, thiab cov kab mob kis kab mob sib sau ua ke hauv tib neeg lub paj hlwb thiab tswj kev tso tawm cov neurotransmitters thiab synaptic kis. Cov kev cai tswjfwm no pab txhim kho lub hlwb kev nco thiab txhim kho spatial cognition thiab mloog.

Tsis tas li ntawd, HSV-1 cov kab mob kis kab mob kuj muaj qee yam kev sib raug zoo nrog lub cev tiv thaiv kab mob thiab cov tshuaj tiv thaiv kab mob. Cov kev tshawb fawb tau pom tias qhov cuam tshuam ntawm HSV-1 cov kab mob kis kab mob ua rau lub cev tiv thaiv kab mob thiab ua haujlwm ntawm "nco T hlwb" hauv lub cev, yog li txhawb lub cev tiv thaiv kab mob. Qhov kev tshawb pom no muaj qhov tseem ceeb tshaj plaws rau kev tshawb nrhiav kev sib raug zoo ntawm HSV-1 thiab kev tiv thaiv tsiaj.

Nyob rau hauv luv luv, kev sib raug zoo ntawm cellular prion virus protein thiab lub cim xeeb muab broad kev tshawb fawb chaw rau yav tom ntej kev tshawb fawb txog kev nco, paj hlwb muaj nuj nqi, thiab kev tiv thaiv kab mob, thiab yuav tsum tau ua lub luag hauj lwm tseem ceeb nyob rau hauv kev tiv thaiv thiab kev kho mob ntawm cov kab mob. Nws tuaj yeem pom tau tias peb yuav tsum txhim kho kev nco, thiab Cistanche tuaj yeem txhim kho kev nco zoo vim Cistanche tuaj yeem tswj hwm qhov sib npaug ntawm cov neurotransmitters, xws li nce qib ntawm acetylcholine thiab kev loj hlob yam, uas tseem ceeb heev rau kev nco thiab kev kawm. Tsis tas li ntawd, Cistanche tseem tuaj yeem txhim kho cov ntshav khiav thiab txhawb nqa cov pa oxygen, uas tuaj yeem ua kom lub hlwb tau txais cov khoom noj txaus thiab lub zog, yog li txhim kho lub hlwb tseem ceeb thiab kev ua siab ntev.

Nyem paub ntxiv los txhim kho kev nco

Txawm hais tias PrPC tau raug thov kom koom nrog ntau lub zog ntawm lub cev, tsuas yog peripheral paj hlwb myelination homeostasis tau lees paub tias yog kev ua haujlwm zoo txog tam sim no.

PrPC misfolding ua rau cov kab mob prion thiab PrPCas tau pom tias muaj kev sib haum xeeb - nplua nuj oligomer-induced neurotoxicity hauv Alzheimer's thiab Parkinson's kab mob nrog rau cov neuroprotection hauv ischemia.

Raws li proteolytic cleavage, PrPC hloov mus rau hauv kev tso tawm thiab txuas cov ntaub ntawv ntawm PrP uas tuaj yeem, nyob ntawm seb muaj cov yam ntxwv ntawm PrPC, tso saib cov khoom tiv thaiv lossis tshuaj lom.

Hauv qhov kev tshuaj xyuas no, peb yuav piav qhia txog prion protein thiab prionprotein fragment zog thiab saib xyuas lawv txoj kev koom tes nrog kev sib tham nrog cov neeg koom tes thiab cov cim qhia hauv myelination, neuroprotection, thiab cov kab mob neurodegenerative.

Cov ntsiab lus: prion protein; prion protein fragments; neuroprotection; myelination; ischemic stroke; kab mob neurodegenerative.

1. Taw qhia

Prion protein (PrP) yog ib qho kev txuag glycoprotein ubiquitous. Nws muaj nyob rau hauv ob daim ntawv; qhov ib txwm lossis cellular isoform, PrPC, thiab cov kab mob sib txuas nrog isoformor scrapie PrP, PrPSc.

Lub luag haujlwm ntawm pathological ntawm PrPSc tau kawm ntau yam hauv priondisease thiab tau raug tshuaj xyuas hauv ntau cov ntaub ntawv [1–3]. PrPC tau qhia nyob rau hauv ntau yam kabmob sib txawv thiab cov ntaub so ntswg nrog kev qhia siab nyob rau hauv nruab nrab thiab peripheralnervous systems.

Nws yog abundantly tam sim no nyob rau hauv lub cell nto ntawm neurons [4-6] thiab koom nyob rau hauv ntau physiological mechanisms. Kev ua haujlwm ntawm cov protein tseem yuav tsum tau elucidated; Txawm li cas los xij, kev tshawb fawb hnyav txuas PrPC rau myelin homeostasis [7], neuroprotection [8,9], circadian atherosclerosis [10,11], hlau ion homeostasis [12,13], mitochondrial homeostasis [14] thiab intercellular signaling [6,15] , 16] ib.

Hauv cov neurons, PrPC muaj nyob rau hauv presynaptic thiab postsynaptic compartments ntawm axon terminals uas nws koom nrog hauv anterograde thiab retrograde axonal thauj [17-20]. PrPC yog cleaved ntawm cell membrane los ntawm proteases, tsim tawm thiab txuas cov ntaub ntawv.

Nyob rau hauv xyoo tas los no, prionprotein thiab prion protein-tso cov ntaub ntawv tau txais kev mloog nyob rau hauv correlation nrog neuroprotection nyob rau hauv cov kab mob neurodegenerative.

Hauv qhov kev tshuaj xyuas no, peb nthuav tawm prion protein thiab prion protein cov ntaub ntawv tso tawm, qhia txog lawv txoj kev koom tes hauv myelination, neuroprotection, thiab neurodegenerative kab mob, thiab sib tham txog cov kev tshawb pom tsis ntev los no hauv daim teb no.

2. Prion Protein

Cov neeg laus PrPC yog tsim los ntawm qhov hloov pauv tsis muaj qauv N-terminal domain (aminoacid residues 23-120) thiab tus qauv C-terminal domain (amino acid residues 121-231).

Nws yog anchored mus rau lub cell membrane nrog ib tug glycosylphosphatidylinositol (GPI) thauj tog rau nkoj [21,22].Qhov hloov tau N-terminal domain muaj ib cheeb tsam octarepeat whereas lub structureddomain muaj peb -helices, ob -sheets, ib tug disulfide daim ntawv cog lus txuas cysteine ​​179and. thiab ob N-glycans ntawm cov amino acid residues 181 thiab 197 [23,24] (Daim duab 1).

PrPC tuaj yeem hloov mus rau hauv daim ntawv-nplua nuj isoform PrPSc, uas yog nquag mus rau autocatalyticconversion thiab aggregation rau hauv insoluble aggregates [22,25,26]. Ib qho txawv txav ntawm cov kab mob pathologic hauv lub hlwb tuaj yeem ua rau kev loj hlob ntawm transmissiblespongiform encephalopathies (TSEs), los yog kab mob prion.

Cov kab mob Prion suav nrog tus kab mob Creutzfeldt-Jakob (CJD), Gerstmann-Sträussler-Scheinker syndrome (GSS), fatalfamilial insomnia (FFI) thiab kuru hauv tib neeg, bovine spongiform encephalopathy nyob rau hauv nyuj, scrapie nyob rau hauv tshis thiab yaj thiab mob nkim kab mob.

Tag nrho cov kab mob prion arerare fatal neurodegenerative disorders. Cov kev kho mob thiab cov kab mob neuropathological ntawm cov kab mob hauv tib neeg zoo ib yam li cov kab mob Alzheimer (AD) xws li kev nco tsis tau sai thiab poob ntawm lub hlwb ua haujlwm nrog rau kev dementia, spongiform deformation ntawm lub hlwb, kev hloov ntawm tus cwj pwm, thiab teeb meem nrog kev txav mus los [15,27] .

Txawm hais tias cov kab mob prion tshwm sim los ntawm kev sib sau ntawm cov tshuaj lom PrPSc sib sau ua ke hauv lub hlwb, cov txheej txheem uas cuam tshuam txog kev hloov pauv ntawm PrPC rau PrPSc thiab kev loj hlob ntawm tus kab mob prion tseem tsis paub.

Sib nrug los ntawm kev ua ib qho substrate rau kev txhim kho cov kab mob prion, PrPC tuaj yeem ua tus receptor rau cytotoxic amyloid- (A ) oligomers [20,28] thiab cov tshuaj lom soluble aggregates ntawm tau protein nyob rau hauv AD thiab lwm yam tauopathies [29,30].

Kuj tseem muaj kev tawm tsam kev tshawb fawb txog PrPC kev khi ntawm -synuclein (-syn) oligomers hauv Parkinson's disease (PD) thiab lwm tus neegynucleinopathies, qhib kev sib cav txog lub luag haujlwm ntawm PrPC hauv toxicity ntawm -synuclein [30–33].

3. Prion Protein Fragments

PrPC tuaj yeem dhau plaub qhov kev hloov pauv hloov pauv, tsim PrP fragments (Daim duab 1).Qhov -cleavage thiab -cleavage tshwm sim nyob rau hauv lub unstructured N-terminal domain whereasthe -cleavage thiab PrP shedding tshwm sim nyob rau hauv tus txheej txheem C-terminal sau.

Sib nrug los ntawm cov lus hais tawm, PrPC tau cleaved nyob rau hauv kev sim nrog phospholipase C, uas cleaved PrPC nyob rau hauv lub GPI thauj tog rau nkoj [34,35]. Qhov chaw ntawm cleavage, qhov ntev ntawm fragment, thiab membrane txuas tso cai rau fragments koom nyob rau hauv ntau yam mechanisms.

3.1. - Cleavage

Qhov -cleavage yog qhov kev tshawb fawb tshaj plaws ntawm PrPC. Nws tshwm sim nyob rau hauv physiological mob nyob rau hauv central hydrophobic cheeb tsam ntawm mature PrPC (amino acid residues 105–120 nyob rau hauv tib neeg ib theem zuj zus 111/112) [36–38] (Daim duab 1).

Lub cleavage tso tawm ib qho ~ 11 kDa fragment N1 whereas lub ~ 18 kDa ib feem C1 tseem txuas nrog lub cell membrane los ntawm GPIanchor [36,39]. Txog tam sim no, tsis muaj qhov tshwj xeeb enzyme lub luag haujlwm rau -cleavage [24,40].

Txawm hais tias qhov chaw cleavage tau txiav txim siab txog hom, -cleavage istolerant mus rau qhov sib txawv ntawm cov cheeb tsam no ntev npaum li nws cov hydrophobicity tseem khaws cia [38].

Cov kev tshawb fawb tau pom tias -cleavage nyob rau hauv tib neeg lub hlwb, nas qauv, thiab neuronal kab lis kev cai tshwm sim nyob rau hauv lub xub ntiag ntawm enzymes ADAM10 thiab ADAM17 [41-43].ADAM10 pab txhawb rau ib tug tsim N1 ntau lawm whereas ADAM17 mas koom nyob rau hauv N1 tsim thaum stimulation [44 , 45] ib. ADAM8 kuj tau pom tias cleavePrPC los ua N1 thiab C1 hauv cov leeg [46].

Lub luag haujlwm ntawm ADAM8, ADAM10, thiab ADAM17 hauv -cleavage kuj tau txais kev txhawb nqa hauv kev tshawb fawb biophysical [47]. Fragment N1 muaj kev ruaj ntseg tsawg; Txawm li cas los xij, nws tau pom tias muaj nyob hauv cov kua hauv lub cev, cov ntaub so ntswg homogenates, lossis cell culture supernatants [39,48,49].

Lub cleavage tau pib xav tias yuav muaj nyob rau hauv acidic endosomal compartments [50,51] tab sis tom qab kev tshawb fawb pom tau hais tias qhov -cleavage tshwm sim thaum lub sij hawm vesicular lag luam ntawm PrPC raws li secretorypathway [52,53].

Lub -cleavage siv PrPC ua substrate, ua rau nws txo qis ntawm cov cell nto. Raws li PrPC kuj yog ib qho substrate rau prion replication thiab tus neeg nruab nrab tseem ceeb ntawm toxicityin prion kab mob, AD, thiab lwm yam kab mob neurodegenerative, cleavage muaj txiaj ntsig zoo.

Qhov hloov tau yooj yim N-terminal ib feem ntawm PrPC yog qhov tseem ceeb rau kev sib cuam tshuam ntawm cov protein nrog cov neeg koom tes uas tswj hwm PrPC uptake hauv kev lag luam [54,55]. Tsis muaj N1, C1 cov ntaub ntawv complexes ntawm lub cell membrane [56] thiab yog ruaj khov thiab pheej nyob rau ntawm lub cell nto tshaj PrPC [50].

Fragment C1 tuaj yeem cleaved ntawm lub xov tooj ntawm tes thiab tso tawm rau hauv qhov chaw extracellular [57]. C1 tau pom tias inhibit prion replication hauv nas [58,59] whereas fragment N1 yog neuroprotective [60,61]; qhov tsis muaj -cleavage yog tshuaj lom rau ob lub hlwb thiab nas [47,62].

3.2. - Cleavage

Qhov -cleavage tshwm sim thaum kawg ntawm octapeptide rov ua dua thaj tsam N-terminal ntawm qhov chaw -cleavage. Qhov-cleavage feem ntau pom nyob rau hauv cov xwm txheej pathological thiab zoo ib yam li -cleavage. Nws zoo li ua tiv thaiv.

Nws tshwm sim nyob ib ncig ntawm aminoacid residue 90, tsim fragment N2 (~ 9 kDa) thiab fragment C2 (~ 20 kDa) [36,37,48,63](Daim duab 1). Lub -cleavage ntawm PrPC yog kho los ntawm reactive oxygen hom (ROS) [37,63–66].

Los ntawm kev tshem tawm ROS, qhov cleavage tiv thaiv cov hlwb los ntawm oxidative kev nyuaj siab [65]. Sib nrug los ntawm ROS, qhov -cleavage yog ntxias los ntawm calpains [67], lysosomal proteases [68,69], lossis txawm ADAM8 [47].

Proteinase K cleaves lub protease-resistant core ntawm PrPSc (PrP27–30) nyob ze txoj hauj lwm 90, tsim ib tug fragment nrog ib tug ntev zoo li C2. Zoo ib yam li fragment C1, fragment C2 kuj beshed los ntawm cell nto [70].

Qhov tsim ntawm cov khoom zoo li no qhia tau hais tias proteasesin koom nrog hauv -cleavage kuj tuaj yeem koom nrog hauv kev sim ntawm tes los rhuav tshemPrPSc [71,72].

3.3. - Cleavage

Qhov tsis ntev los no nrhiav pom protease cleavage ntawm PrPC yog -cleavage. Lub cleavagesite hauv PrPC tseem yuav txiav txim siab tab sis qhov ntau thiab tsawg ntawm cov khoom tawg N3 (~ 20 kDa) thiab GPI-aschored fragment C3 (~ 5 kDa) qhia tias protein cleavage tshwm sim hauv cheeb tsam ntawm cov amino acid residues 170 thiab 200 [73, 74] (Daim duab 1).

Cov kev tshawb fawb qhia tias qhov -cleavage tshwm sim lig nyob rau hauv txoj kev secretory ntawm ib qho unglycosylated protein nyob rau hauv muaj cov tswv cuab ntawm matrix metalloproteases (MMP) tsev neeg [73].

Yog vim li cas qhov -cleavage tshwm sim tsuas yog nyob rau hauv unglycosylated PrPC yog npaj los ntawm steric hindrance ntawm proteases los ntawm glycans nyob ze ntawm lub proposed cleavage site [40,75].

Cov-cleavage tau pom muaj nyob rau hauv ntau hom, cov ntaub so ntswg, thiab cell kab lis kev cai qauv. Qhov kev txiav txim siab ntawm nws lub luag haujlwm yuav tsum tau kawm ntxiv txawm hais tias qhov qhia tau hais tias muaj ntau ntawm fragment C3 hauv lub hlwb CJD tuaj yeem ua rau muaj qhov tseem ceeb ntawm pathogenic [73].

3.4. Kev tshem tawm ntawm Prion Protein

Tseem muaj qhov tseem ceeb cleavage ntawm PrP nyob ze rau C-terminus. Lub cleavage sheds PrP mus rau hauv lub extracellular qhov chaw, tawm hauv ib tug me me ntawm cov amino acid residues ntawm lub xov tooj ntawm tes.

Cov cleavage tau piav nyob rau hauv kev tshawb fawb thaum ntxov [35,39,76,77] tab sis tau txais kev saib xyuas ntau dua nyob rau xyoo tas los no vim muaj kev koom tes ntawm PrP hauv cov kab mob [40,63,78–83].

Zoo ib yam li -cleavage, qhov tso tawm ntawm PrP tshwm sim nyob rau hauv lub xub ntiag ntawm enzymes los ntawm tsev neeg ADAM. Hauv vitro thiab hauv vivo kev sim qhia tias ADAM9 thiab ADAM10 tau koom nrog hauv cov txheej txheem ntawm kev sib cais thiab kev tshem tawm ntawm PrP [47,84–86] qhov twg ADAM10 yog thawj sheddase rau PrP thiab ADAM9 yog tus modulator ntawm ADAM10 kev ua [24 ].Shed PrP thawj zaug txiav txim siab hauv hamsters.

Nyob rau hauv prion-mob hlwb ntawm hamsters, shedPrP sawv cev kwv yees li 15% ntawm PrPSc molecules [76]. Ib qho kev soj ntsuam ntxiv tau pom tias ADAM10 cleaved shed PrP ntawm Gly228 thiab Arg229 thiab tsim los PrP uas tau txiav tawm ntawm Gly228 [84].

Ib qho kev soj ntsuam tshawb xyuas qhov cleavage site profile ntawm ADAM10 tau qhia tias qhov kev sib cais tsis yog tshwm sim los ntawm qhov sib txawv [87].

Yog li ntawd, ADAM10protease tuaj yeem tsim cov kev hloov pauv ntawm PrP nyob ntawm seb muaj protein ntau thiab kev sib haum xeeb. Jansen thiab cov neeg ua haujlwm tau piav qhia txog qhov muaj nyob ntawm cov ntaub ntawv PrP uas tsis muaj qhov xaus nrog Tyr225 thiab Tyr226 hauv cov neeg mob prion [88].

Cov kws sau ntawv qhia txog ob tus neeg mob uas muaj tus kab mob prion uas tau nres kev hloov pauv ntawm txoj haujlwm Y226X thiab Q227X thiab nthuav tawm cov ntaub ntawv ntsig txog. Siv cov tshuaj monoclonal antibody V5B2 [89] uas tshwj xeeb khi rau ib feem ntawm PrP xaus nrog Tyr226, peb tau piav qhia txog qhov muaj nyob ntawm daim ntawv dawb ntawm PrP npe PrP226 * [90–94].

Kev faib tawm ntawm PrP226 * hauv tib neeg lub hlwb tau cuam tshuam nrog kev faib tawm ntawm PrPSc [90,94]. Vim tias muaj ntau tshaj li ib daim ntawv los, peb xav tias qhov chaw proteolytic nyob rau hauv tib neeg ib ntus yog qhov tshwj xeeb ntawm cov amino acid residues 228 thiab 229 tab sis nyob rau hauv qhov sib thooj ntawm C-terminus [95] (Daim duab 1).

Tsis ntev los no, Linsenmeier et al. luam tawm ib qho kev kawm tiav ntawm lub tshuab stimulating PrPC proteolytic shedding [81]. Siv cov qauv tsiaj thiab kev tswj hwm, lawv tau pom tias PrP tso tawm tsis zoo cuam tshuam nrog kev hloov pauv hloov pauv thiab qhov tso tawm PrP muaj ntau nyob rau hauv amyloid plaques.

Lawv kuj tau kawm txog kev cuam tshuam ntawm kev khi ntawm PrP-qhia cov tshuaj tiv thaiv rau PrPC ntawm kev ua kom muaj zog. Kev khi ntawm tag nrho cov tshuaj tiv thaiv PrP rau C-terminal structured domainof PrPC lossis ib leeg-chain antibody derivatives, qhia rau rov ua dua epitopes nyob rau hauv thaj tsam octarepeat ntawm N-terminal domain stimulated shedding, thaum lub binding ntawm tag nrho cov anti-PrP cov tshuaj tiv thaiv rau octarepeat. thaj tsam ntawm N-terminal domain kaw lub N-terminal domain qauv thiab evoked PrPC nto pawg, endocytosis thiab degradation hauv lysosomes [81].

4. Prion Protein thiab Myelination

PrPC tau nthuav tawm ntau nyob rau hauv lub hauv paus paj hlwb (CNS) thiab lub paj hlwb peripheral [4,5]. Kev tshawb fawb hauv lub hlwb primate, nas hlwb, thiab transgenic mices qhia tau hais tias nws yog enriched raws axons thiab nyob rau hauv presynaptic terminals uas nws koom nyob rau hauv anterograde thiab retrograde axonal thauj [4,17,18,96–98].

Kev tshem tawm hauv thaj tsam PrPC cleavage pom tias muaj kev demyelination hnyav nyob rau hauv ob qho tib si qaum qaum thiab cerebellar whitematter hauv vivo [99,100] Tom qab ntawd, nws tau lees paub tias axonal PrPC thiab nws -cleavage yog tsim nyog rau pro-myelination nyob rau hauv peripheral paj hlwb [101].

Siv tus qauv co-isogenicPrP-knockout nas, Kuffer li al. tshawb pom tias axonal PrPC txhawb nqa myelinmaintenance hauv trans los ntawm kev khi rau qhov adhesion G-protein-coupled receptor Adgrg6 onSchwann hlwb nrog N-terminal hloov tau tus Tsov tus tw [7].

Lawv kuj tau lees paub tias cov nas tsis muaj PrPC tau tsim kho mob demyelinating neuropathy, uas qhia tias myelination homeostasis nyob rau hauv lub paj hlwb peripheral yog ib qho kev ua haujlwm ntawm lub cev ntawm PrPC [7].

Kev saib xyuas Myelin tau pom tias tau tswj hwm los ntawm kev khi ntawm N-terminalreleased fragment ntawm PrPC (txawm tias N1 los yog tso PrP) rau Adgrg6 ntawm Schwann hlwb.

Qhov kev sib cuam tshuam tau qhib Adgrg6, nce qib cellular ntawm cAMP, thiab ua rau muaj kev cuam tshuam kev cuam tshuam uas txhawb nqa myelination [7]. Cov kev cai ntawm peripheral myelinmaintenance los ntawm PrPC tau lees paub nyob rau hauv tsib txawv PrP-knockout nas qauv strainsthat tsim lig-pib peripheral neuropathy [101-103].

Tsis ntev los no, muaj kev sim tsim kho rau cov kab mob peripheral demyelinating raws li kev khi ntawm N-terminal domain ntawm PrPC thiab Adgrg6 [104]. Hauv txoj kev tshawb no, lawv tau tsim ib qho immunoadhesin molecule uas muaj ob qhov hloov tau N-terminal domains ntawm PrPC txuas rau acrystallizable fragment (Fc) ntawm immunoglobulin G1 (FT2Fc) [104].

Cov molecule tau pom tias muaj cov tshuaj pharmacokinetic zoo thiab pom tau tias muaj peev xwm hauv vitro tab sis ua tsis tau zoo rau cov kab mob atherapeutic ntawm cov cim qhia ntawm demyelination hauv PrP-knockout nas [104].

PrPC kuj tau kawm nyob rau hauv kev sib txuas rau peripheral myelin kev loj hlob thiab regeneration tom qab paj hlwb raug mob [105]. Raws li PrP tau pom tias yuav siv tau rau hauv cov txheej txheem no, nws tuaj yeem xav tias PrP tsis muaj lub luag haujlwm tseem ceeb hauv cov txheej txheem kho cov hlab ntsha peripheral lossis nws qhov tsis tuaj yeem raug them los ntawm lwm cov ligands [105].

Myelination thiab lwm yam physiological lub luag hauj lwm ntawm PrPC tau siv zog kawm onanimal qauv nrog ib tug knocked-tawm los yog knocked-down PrP noob qhia.

Cov kev tshawb fawb tau pom tias muaj kev cuam tshuam tsis zoo hauv nas [102,106–109], nyuj [110], thiab tshis [68,111,112] whereas kev tshawb fawb ntawm PrP-knockout nas lossis tshis pom qhov tsis xws luag hauv lub paj hlwb thiab rhiab heev rau oxidative stress [6,1,111] Ntau tus qauv PrP-knockout nas tau tsim nrog keeb kwm sib xyaw [106,109,114–116].

Raws li cov kev tshawb fawb tsis yog reproducible ntawm cov qauv, qhov no yuav ua rau cov lus nug ntawm seb puas muaj cov phenotypes tau tshwm sim vim yog polymorphisms hauv cov noob flanking Prnp lossis qhov tshwm sim ntawm PrPC tsis tuaj. Txhawm rau zam qhov teeb meem no, nws yuav raug nquahu kom rov ua qhov kev sim tseem ceeb uas siv cov co-isogenic PrPknockout nas.

Txawm hais tias lub luag haujlwm ntawm PrPC hauv CNS yuav tsum tau qhia meej, PrPC thiab PrPC-tso tawm fragments yog qhov tseem ceeb hauv peripheral paj hlwb myelin homeostasis tab sis lawv yuav tsum tau muab tshem tawm hauv cov hlab ntsha rov qab.

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