Cov GTPases Me Me Ntawm Cov Tsev Neeg Rab Thiab Arf: Cov Txheej Txheem Tseem Ceeb Ntawm Kev Lag Luam Hauv Kev Lag Luam Hauv NeurodegenerationⅢ
Mar 29, 2023
3. Arf GTPases hauv Neurodegeneration
Arf GTPases yog ib tsev neeg ntawm 29 tus tswv cuab tau faib ua cov tsev neeg sib txawv: Arf1- 6, Arf-zoo li cov proteins (Arl), SARs, thiab Trim23 [9,126,127]. Arf GTPases txawv ntawm Ras, Rho, thiab Rab tsev neeg raws li lawv muaj N-terminal txuas ntxiv ntawm txog 14 amino acids uas tuaj yeem hloov kho cov kev hloov pauv. Hauv qhov no, Arf GTPases tuaj yeem ua tau N-myristoylated thaum Arl GTPases tuaj yeem ua myristoylated, palmitoylated, lossis acetylated [9]. Arf GTPases tswj cov txheej txheem ntawm tes xws li kev lag luam bidirectional ntawm daim nyias nyias (secretion thiab endocytosis), metabolism ntawm lipids, motility, faib, apoptosis, thiab noob transcription [9,127].
Nyem rau cistanche tubulosa capsules rau Alzheimer's kab mob thiab Parkinson tus kab mob
Txawm li cas los xij, lawv lub luag haujlwm tseem ceeb yog kev nrhiav neeg ua haujlwm ntawm lub tsho tiv no cov protein thiab cov complexes thaum lub sij hawm vesicle tsim nyob rau hauv daim nyias nyias, tshwj xeeb tshaj yog nyob rau hauv lub Golgi [9]. Yog li, Arf GTPases, nrog rau lawv cov GEFs thiab GAPs, yog nyob rau hauv plasma membrane, endosomes, lipid droplets, mitochondria, thiab lysosomes [9].
Zoo li txhua GTPases ntawm Ras superfamily, cov haujlwm ntawm Arf GTPases yog tswj los ntawm GEFs, GAPs, thiab GDIs. Hauv tib neeg, 15 Arf GEFs tau piav qhia, thiab tau muab faib ua rau tsev neeg nyob ntawm lawv cov npe: GBF, BIGs, Cytohesins, EFA6 / Psd, BRAG / IQSec, thiab FBX [9]. Tag nrho lawv sib koom ua ke ntawm Sec7 catalytic domain [9,128,129]. Hais txog Arf GAPs, lawv raug faib ua 10 subtypes: ArfGAP1, ArfGAP2/3, ADAP1/2, SMAP1/2, AGFG1/2, GIT1/2, ASAP1-3, ACAP1-3, ARAP{ {21}} thiab AGAP1-11 [130–132]. Lawv yog tus cwj pwm los ntawm lawv cov Arf GAP catalytic domain, txawm hais tias ib tsev neeg ntawm cov proteins hu ua ELMOD tau pom tias muaj GAP cov haujlwm ntawm qee qhov Arf GTPases yam tsis muaj Arf GAP domain [133–135].
Tsis tas li ntawd, Arf GTPases tuaj yeem tswj hwm los ntawm kev hloov pauv tom qab kev hloov pauv xws li phosphorylation lossis ubiquitination [9]. Ntau yam Arf GEFs thiab GAPs tau piav qhia los ua lub luag haujlwm tseem ceeb hauv lub paj hlwb. Piv txwv li, Arf6 GAP, tseem hu ua ACAP3, tau pom tias tswj cov neurite outgrowth hauv hippocampal neurons hauv nas [136]. Arf6 EFA6 GEF koom nrog hauv arborization ntawm dendrites thiab tsim ntawm dendritic spines [137].
Ntxiv mus, kev hloov pauv hauv GEF BRAG1 / IQSec2 tau cuam tshuam nrog kev tsis taus X-txuas kev txawj ntse [138]. Lwm qhov piv txwv yog cov nas nrog Schwann cell-specific GEF BIG1 knockout zaub txo myelin thickness [139]. Tag nrho cov kev tshawb fawb no qhia txog qhov tseem ceeb ntawm Arf GTPases, nrog rau lawv cov tswj hwm hauv lub paj hlwb. Txog Arf GTPase lub ntsiab effector molecules, lawv yog cov khoom ntawm vesicle txheej, xws li COP I, adapter proteins (AP), GGA, thiab MINT, uas yog cov feem ntau kawm [140]. COP I yog vesicle-coated protein complex [141]. AP{10}}, AP-3, thiab AP{12}} yog clathrin adapter proteins [9,140]. GGAs koom nrog TGN. Thaum kawg, MINTs cuam tshuam nrog Munc18, neuronal protein xav tau rau exocytosis ntawm synaptic vesicles [142].
Arf GTPases tau cuam tshuam rau cov kab mob ntawm lub paj hlwb, xws li ALS, kab mob retinal, thiab kab mob Creutzfeldt-Jakob [143]. Ntxiv mus, Arf GTPases yog txuam nrog AD, raws li MINTs tswj APP kev lag luam [35] thiab GGAs cuam tshuam nrog BACE1 los tswj APP ua [144] (Daim duab 3)
3.1. Arf/MINT thiab APP Trafficking thiab ua
MINTs yog ib tsev neeg ntawm peb cov proteins uas tau qhia tshwj xeeb hauv cov ntaub so ntswg neuronal. Lawv yog cov khoom tseem ceeb rau fusion ntawm neuronal synaptic vesicles [142,145]. MINT proteins ncaj qha khi rau Arf-GTP thiab colocalize nrog APP hauv TGN cheeb tsam [35]. MINT overexpression hauv HEK293 hlwb nce Arf GTPase-mediated APP protein ntau [35]. Hloov pauv, siRNA tshwj xeeb ntsiag to ntawm MINT3 hauv HeLa hlwb txo qis APP protein ntau. Qhov no tau qhia txog Arf/MINT axis tswj APP kev lag luam [35]. Lwm txoj kev tshawb fawb pom tau hais tias MINT3 colocalized nrog APP hauv purified APP muaj vesicles hauv SH-SY5Y neuroblastoma cell kab [146]. SiRNA silencing ntawm MINT3 cuam tshuam rau APP kev lag luam, nrog rau kev ua haujlwm, ua rau muaj kev nce ntxiv hauv A 1-40 zais cia [146].
Tsis ntev los no, ib txoj kev tshawb fawb hauv N2a / APP695 nas neuroblastoma cell kab tau pom tias kev kho mob nrog txiv maj phaub roj txo mRNA thiab protein ntau ntawm Arf1. Tsis tas li ntawd, lawv cov txiaj ntsig tau pom tias A 1-40 y A 1-42 qib zais cia tau txo qis [36]. Tag nrho cov kev tshawb fawb no qhia tias Arf GTPase, nrog rau nws cov nyhuv molecule MINT3, tuaj yeem yog lub hom phiaj kho mob los pab tswj cov kab mob A secretion hauv AD.
3.2. Arf/GGA/BACE1
GGAs koom nrog hauv kev thauj thiab txheeb cov proteins hauv TGN [147]. Ib qho ntawm txoj haujlwm zoo tshaj plaws ntawm kev kawm ntawm GGAs yog coj mus rau kev thauj mus los ntawm ubiquitinated proteins mus rau txoj kev endolysosomal, vim lawv muaj ubiquitin-binding qhov chaw [148-150]. Nws tau raug piav qhia tias GGA3 khi rau ubiquitinated BACE1 secretase los tswj nws cov proteasomal degradation [151]. Hauv qhov no, ectopic qhia ntawm GGA3 hauv GGA3-knock-out H4 neuroglioma hlwb thaiv BACE1 tsub zuj zuj, nrog rau A 1-40 secretion [151]. Yog li ntawd, lub zog ntawm Arf / GGA3 axis kev ua haujlwm tuaj yeem txo BACE1 qib thiab yog li, A secretion. Txawm li cas los xij, ib txoj kev tshawb fawb pom hauv HEK293 hlwb cotransfected nrog APP695 thiab BACE, uas GGA1 sequesters APP ua ke nrog BACE1 rau hauv Golgi [152].
Yog li ntawd, BACE1 cov txheej txheem APP nce qib CTF. Curiously, tsis yog cov qib intracellular lossis qhov tso tawm ntawm A 1-40 tau nce. Cov kws sau ntawv tau txiav txim siab tias GGA1 sequesters lub APP rau hauv Golgi ua ke nrog BACE1, qhov chaw -cleavage tshwm sim, thiab GGA1 kuj tiv thaiv cov CTF fragments los ntawm kev thauj thiab ua tiav los ntawm -secretase. Nyob rau hauv txoj kev no, txawm hais tias CTF nce, GGA1 yuav tsis zoo tswj nws cov kev ua los ntawm -secretase thiab, yog li ntawd, tiam ntawm A 1-40 [152]. Hauv tib kab, lwm txoj kev tshawb fawb hauv HEK293 thiab N2a xov tooj ntawm tes tau qhia tias GGA overexpression ua rau txo qis hauv kev tso tawm ntawm soluble APP alpha (sAPP), sAPP, thiab A . siRNA silencing ntawm GGA thim rov qab cov nyhuv no [144].
3.3. Arl8 thiab Neuroprotection Tawm tsam A
Arl8 GTPase txhawb nqa pre-synaptic vesicular thiab endocytic macromolecule khiav mus rau lysosomes [153,154]. Ntau yam effector molecules yog recruited rau lysosomal membranes los ntawm Arl8-GTP [155]. Piv txwv li, lub HOPS complex yog lub luag hauj lwm rau fusion ntawm compartments nyob rau hauv lub lig endocytic txoj kev [153,156,157]. Lwm cov tshuaj molecule tau piav qhia rau Arl8 hauv cov tsiaj nyeg yog SKIP/PLEKHM2, uas yog cov protein txuas uas tau txais cov kinesin -1 rau lysosomal membranes [155,158]. Nws tau raug piav qhia tias kev ntsiag to ntawm Arl8 hauv C. elegans neurons provokes A -mediated neurodegeneration [37]. Ntawm qhov tsis sib xws, qhov overexpression ntawm Arl8 ib feem thaiv qhov no neurodegeneration.
Cov kws sau ntawv tau pom tias lub luag haujlwm neuroprotective ntawm Arl8 nyob ntawm nws lub xeev ntawm kev ua kom. Constitutively nquag ArlQ75L ib nrab txo cov neurodegeneration, qhov tseem ceeb-tsis zoo ArlT34N tsis muaj kev tiv thaiv zoo [37]. Cov kws sau ntawv qhia tias Arl8 tuaj yeem cuam tshuam cov txheej txheem neurodegenerative los ntawm kev ua kom autophagy [37,159].
3.4. ArfGAP1/LRRK 2
LRRK2 yog multidomain protein uas nthuav tawm cov haujlwm kinase nrog rau kev ua GTPase [160], tau piav qhia los ntawm ArfGAP1 hauv HEK293 thiab lub hlwb rho tawm los ntawm nas [161]. Cov kev cai ArfGAP1/LRRK2 yog sib txuam, vim LRRK2 tuaj yeem phosphorylate ArfGAP1 thiab nce nws cov haujlwm. Ntxiv mus, ArfGAP1, sib nrug los ntawm activating GTP hydrolysis, kuj nce LRRK2 kinase kev ua ub no, tawm tswv yim tias ArfGAP1 kev ua ub no tuaj yeem cuam tshuam rau qhov kev ua kom kinase no [161]. Nws paub tias thawj cov neurons los ntawm LRRK2G2019S nas tso tawm neurite retraction. Stafa thiab cov neeg koom tes tau cawm cov phenotype no los ntawm kev ntsiag to ArfGAP1 [161]. Yog li, qhov GAP no tuaj yeem yog lub hom phiaj kho mob rau PD [161].
4. Kev xav yav tom ntej
Lub hom phiaj ntawm cov tshuaj siv rau kev kho mob ntawm AD thiab PD yog txhawm rau txhim kho kev paub thiab kho cov tsos mob. Yog li, FDA pom zoo tshuaj rau ob qho tib si kab mob suav nrog cholinesterase inhibitors thiab N-Methyl D-Aspartate (NMDA) receptor antagonists [162]. Txawm li cas los xij, cov kev kho mob tsis cuam tshuam txog keeb kwm thiab kev loj hlob ntawm tus kab mob. Hauv qhov no, qee txoj hauv kev tam sim no tau kawm kom txo qis A ntau lawm, txo qhov sib sau lossis txhim kho nws qhov kev tshem tawm ntawm ib sab, thiab inhibit Tau phosphorylation ntawm lwm tus [162], thiab cov tshuaj tshiab dopaminergic tam sim no raug sim rau PD [162. ].
Ob yam kab mob, AD thiab PD, qhia cov yam ntxwv xws li kev tsim thiab kev sib sau ntawm cov tshuaj lom peptides. Txawm li cas los xij, ob peb txoj kev tshawb fawb tau tsom mus rau lub luag haujlwm ntawm daim nyias nyias thiab vesicular kev lag luam nyob rau hauv tiam, tsub zuj zuj, thiab tshem tawm ntawm cov peptides. Tshwj xeeb, txoj haujlwm ntawm Rab thiab Arf GTPases nyob rau hauv cov txheej txheem no yuav tsum tau muab kev saib xyuas ntau dua, thiab tsom mus rau lawv tuaj yeem yog txoj hauv kev zoo. Ib lub tswv yim tuaj yeem hloov kho Rab thiab Arf GTPase kev ua haujlwm nyob ntawm lawv lub xeev hauv pathology. Kev nthuav qhia ntawm cov qauv ua haujlwm zoo lossis tseem ceeb-tsis zoo ntawm cov GTPases no yuav yog lwm txoj hauv kev.
Piv txwv li, constitutively active ArlQ75L txo A -induced neurodegeneration hauv C. elegans [37]. Lwm qhov piv txwv yog daim ntawv tseem ceeb-tsis zoo ntawm Rab7A, uas ib nrab thaiv Tau secretion [29]. Ntxiv mus, lub hom phiaj ntawm kev qhia los ntawm siRNA Silencing cov tswv yim tuaj yeem ua qhov kev kho mob zoo. Rab7A silencing los ntawm siRNA tau raug pov thawj tias muaj txiaj ntsig zoo hauv kev txo qis ntawm Tau secretion ib yam nkaus [29]. Ib txoj kev tshawb fawb tsis ntev los no tau hais qhia tias kev hloov kho Arf GTPases tuaj yeem yog txoj hauv kev ua tau. Kev kho cov roj txiv maj phaub hauv N2a / APP695 hlwb txo qis Arf1 mRNA thiab cov protein ntau, uas ua rau txo qis hauv A 1-40 thiab A 1-42 qib secretion [36].
Tsis tas li ntawd, kev tsom mus rau PTMs uas tso cai rau GTPases rau kev thauj mus los ntawm cov cellular daim nyias nyias tuaj yeem yog txoj hauv kev zoo rau cov tsev neeg Rab thiab Arf, vim lawv yog cov tswj hwm tseem ceeb ntawm daim nyias nyias thiab vesicle kev lag luam. Lub tswv yim no twb tau ua pov thawj tias yuav siv tau rau lwm tsev neeg ntawm Ras superfamily [5,163]. Piv txwv li, inhibition ntawm Rho tsev neeg PTMs los ntawm lovastatin txhawb kev kho myelin [163]. Cov kev cai ntawm GEFs, GAPs, thiab GDIs uas tswj cov Rab thiab Arf GTPases yuav yog ib txoj hauv kev ntxiv rau kev kho cov kab mob neurodegenerative. Thaum kawg, peptides uas cuam tshuam nrog cov protein-protein kev sib cuam tshuam ntawm GTPases thiab lawv cov nyhuv effector molecule yog ib qho kev cog lus, vim tias kev sib cuam tshuam tshwj xeeb tuaj yeem cuam tshuam yam tsis cuam tshuam rau GTPase kev cuam tshuam nrog lwm cov tshuaj molecules [5]. Qhov teeb meem nyob rau hauv qhov tseeb tias qee tus Rab thiab Arf GTPases tuaj yeem qee zaum muaj lub luag haujlwm neuroprotective, thaum lwm lub sijhawm lawv tuaj yeem ua rau neurotoxic.
Piv txwv li, Rab5 overexpression tau pom tias nce A 1-40 thiab A 1-42 secretion [22] thiab Rab7 zoo li pab txhawb rau Tau secretion [29]. Txawm li cas los xij, kev khiav tsheb endolyssomal tswj los ntawm Rab5 thiab Rab7 zoo li pom zoo rau kev tshem tawm ntawm A [23,24]. Lwm qhov piv txwv yog Rab1.
Whereas Rab1 tau piav qhia los tiv thaiv GA fragmentation [16,17], nws tsis ntev los no tau tshaj tawm tias muaj peev xwm ua rau muaj qhov tawg ntawm cov neurons los ntawm tib neeg PD cov neeg mob [18]. Lub xub ntiag ntawm GTPases nrog lub luag haujlwm tsis sib xws hauv cov kab mob neurodegenerative ntxiv cuam tshuam rau kev txhim kho ntawm kev kho mob. Lub xeev pathological ntawm kev ua kom muaj zog hauv txhua kis tshwj xeeb yuav tsum tau muab coj los txiav txim siab thaum tsom mus rau GTPases me me raws li cov hom phiaj kho mob. Tsis tas li ntawd, nws yog ib qho tseem ceeb uas yuav tau piav qhia tag nrho cov teeb liab cascade tswj los ntawm txhua GTPase nyob rau hauv txhua yam pathological mob ua ntej txiav txim siab GTPase raws li lub hom phiaj kho.
Txawm hais tias muaj ntau qhov kev taw qhia cascades tau piav qhia hauv neurodegeneration hauv Ras thiab Rho tsev neeg [5], txoj hauv kev tswj hwm los ntawm Rab thiab Arf tsev neeg xav tau kev kawm tob. Yog li, cov lus piav qhia ntawm qhov tseeb axis tswj txhua qhov tshuaj lom neeg yuav pab peb txheeb xyuas cov hom phiaj kho mob. Xav txog qhov no, daim teb yuav tsum tau ua ntej piav qhia txog cov cim qhia tseeb cascades tswj los ntawm Rab thiab Arf GTPases hauv neurodegeneration txhawm rau txheeb xyuas lub hom phiaj muaj peev xwm. Txawm li cas los xij, tsis yog nws tseem ceeb heev los piav qhia txog cov teeb liab cascades, tab sis kev txheeb xyuas qhov chaw ntawm lub pas dej tshwj xeeb uas tau qhib rau hauv lub xov tooj ntawm tes yog qhov tseem ceeb [5]. Tsis tas li ntawd, qhov cuam tshuam ntawm glial hlwb yuav tsum tsis txhob muab pov tseg.
Feem ntau cov kev tshawb fawb hauv Rab thiab Arf GTPases tau ua tiav hauv cov hlwb neuronal, tsis quav ntsej txog kev koom tes ntawm glial hlwb hauv cov kab mob ntawm cov kab mob neurodegenerative. Piv txwv li, cov kab mob microglial nthuav tawm cov ntim ntau ntawm cov khoom lag luam membrane thaum lawv nquag koom nrog kev tshem tawm cov protein ntau. Yog li ntawd, cov txheej txheem tshwj xeeb tsom rau cov hlwb glial tuaj yeem yog qhov kev xaiv kho tau zoo. Ntxiv nrog rau qhov tseem ceeb ntawm kev tshawb nrhiav kev kho mob, cov kev tshawb fawb yuav tsum tsom mus rau kev tshawb fawb txog kev tshawb pom ntxov ntawm cov kab mob neurodegenerative. Piv txwv li, ib qho kua biopsy-raws li kev kuaj mob thaum ntxov yuav txhim kho qhov tshwm sim ntawm cov kab mob neurodegenerative thiab cov kws tshawb fawb tam sim no sim nrhiav biomarkers rau kev tshawb pom ntxov [164].
Txawm li cas los xij, yog tias tus biomarker yuav tsum muaj nyob hauv cov ntshav, nws yuav tsum muaj peev xwm hla cov ntshav-hlwb barrier [165]. Lwm qhov teeb meem yog tias qhov concentration ntawm biomarker hauv cov ntshav tuaj yeem qis dua hauv cov kua cerebrospinal; Piv txwv li, A concentrations yog 10-fold qis hauv plasma [165]. Yog li, cov txheej txheem rhiab heev yuav tsum tau ua kom pom cov biomarkers hauv cov ntshav. Txawm hais tias cov teeb meem no, qhov kev kuaj mob ua kua biopsy-raws li yuav sai sai no hauv thaj tsam ntawm cov kab mob neurodegenerative [164].
5. Xausions
Lub Ras superfamily ntawm GTPases tau ntev tsis pom zoo ua cov neeg muaj peev xwm hauv cov kab mob neurodegenerative. Tsis ntev los no, peb tau tshuaj xyuas lub luag haujlwm ntawm Ras thiab Rho cov tsev neeg, nrog rau lawv cov kev tswj hwm thiab cov txiaj ntsig molecules, raws li cov neeg koom nrog hauv cov kab mob neurodegeneration [5]. Thaum nws los txog rau Rab thiab Arf GTPases, thaj chaw tau tshawb nrhiav tsawg dua, thiab qee qhov kev tshawb fawb tau cuam tshuam cov hloov pauv molecular nrog AD thiab PD. Txawm li cas los xij, cov kev tshawb fawb no yog qhov qhia meej tias cov tsev neeg Rab thiab Arf koom nrog hauv cov kab mob ntawm cov kab mob neurodegenerative. Nyob rau hauv ib lub tswv yim dav, Rab GTPases nyob rau hauv physiological tej yam kev mob yog lub luag hauj lwm rau vesicular thauj thiab membrane trafficking [38].
Lawv tswj kev ncaj ncees ntawm GA, kev ua thiab kev lag luam ntawm cov tshuaj lom peptides xws li APP, thiab kev thauj mus los ntawm cov proteins xws li membrane receptors, thiab autophagy. Hais txog Arf GTPases, lawv lub luag haujlwm tseem ceeb yog tswj kev tsim cov vesicle, txawm hais tias lawv kuj yog cov tswj hwm ntawm daim nyias nyias cov kev lag luam bidirectional [9]. Ua li no, lawv tswj kev lag luam ntawm cov protein xws li APP thiab BACE1. Peb cia siab tias yav tom ntej kev tshawb fawb yuav tso cai rau peb los ua tus yam ntxwv ntawm tag nrho cov teeb liab cascades tswj los ntawm Rab thiab Arf GTPases hauv neurodegeneration, thiab qhov no yuav cia siab tias yuav pab txhawb kev txhim kho cov tswv yim kho mob. Txawm li cas los xij, nws yuav tsum tau qhia tias feem ntau cov kev tshawb fawb tau ua tiav ntawm cov hlwb neuronal, tsis quav ntsej txog kev koom tes ntawm glial hlwb hauv cov kab mob ntawm neurodegeneration. Yog li, lub luag haujlwm ntawm GTPases hauv AD thiab PD yuav tsum tau kawm tsis yog hauv cov neurons nkaus xwb tab sis hauv lub paj hlwb tag nrho.
Vim li cas noj Cistanche yog qhov zoo rau Alzheimer's disease thiab Parkinson's disease
Cistanche muaj ntau cov tshuaj nquag uas tau pom tias muaj cov teebmeem neuroprotective, uas tuaj yeem pab tiv thaiv lossis ua kom qeeb ntawm Alzheimer's disease thiab Parkinson's disease. Cov tebchaw no suav nrog echinacoside, acteoside, thiab verbascoside, uas tau pom tias muaj cov tshuaj tiv thaiv kab mob thiab antioxidant uas tuaj yeem tiv thaiv cov neurons los ntawm kev puas tsuaj thiab txo qhov mob hauv lub hlwb. Tsis tas li ntawd, cistanche tau pom tias nce qib ntawm acetylcholine, neurotransmitter uas tseem ceeb rau kev kawm thiab kev nco, uas tuaj yeem txo qis hauv Alzheimer's disease. Thaum xav tau kev tshawb fawb ntxiv kom nkag siab txog cov txiaj ntsig zoo ntawm cistanche los tiv thaiv cov kab mob no, cov kev tshawb pom thawj zaug tau cog lus tseg.
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