GTP Energy Dependence Of Endocytosis Thiab Autophagy nyob rau hauv Lub Laus Brain Thiab Alzheimer's Disease Ⅱ

Feem ntau GTPase qhia txoj hauv kev hauv autophagy: macroautophagy (mitophagy), microautophagy, thiab CMA

GTPase superfamily suav nrog ntau cov proteins uas ua raws li cov hloov pauv molecular los ntawm kev khi thiab hydrolyzing GTP molecules rau tethering, docking, thiab fusion ntawm vesicles rau lub hom phiaj membranes [46]. Kev hloov pauv hauv GTPase muaj feem cuam tshuam nrog kev hloov pauv hauv kev lag luam ntawm cov khoom thauj [47]. Kev hloov ntawm lub xeev "active" (GTP-bound GTPase) thiab lub xeev "tsis ua haujlwm" (GDP-bound GTPase) yuav tsum muaj guanine nucleotide exchange factor (GEF) thiab GTPase activating protein (GAP) [48] (Fig. 3) , termed the Rab GEF/GAP cascade [22]. Rau ntau GTPases, lub neej ntawm lub tshuab txais, GTP-bound xeev ntseeg tau los ua tus tswj xyuas hauv kev txiav txim siab lub sijhawm ua kom muaj roj ntsha xws li daim nyias nyias fusion thiab cov teeb liab hloov. Txawm li cas los xij, kev ua haujlwm zoo ntawm GTPases kuj tseem tuaj yeem raug txwv los ntawm kev txo qis hauv cov qib ntawm GTP. Autophagosome tsim muaj cov neeg hauv tsev neeg Rab1, Rab5, Rab7, Rab9A, Rab11, Rab23, Rab32, thiab Rab33B. Rab9 yog yuav tsum tau nyob rau hauv non-canonical autophagy. Rab7, Rab8B, thiab Rab24 muaj lub luag haujlwm tseem ceeb hauv autophagosome maturation. Rab8A thiab Rab25 koom nrog hauv qhov tsis paub txog ntawm autophagy [22]. Rab11 yog xav tau rau exocytosis [49]. Ua tsis tiav autophagy yog txuam nrog ntau yam mob tsis zoo xws limetabolic kev nyuaj siabthiab aggregation ntawm cov proteins txuam nrog neurodegenerative mob xws liAlzheimer tus kab mob. Rab8b muaj lub luag haujlwm tseem ceeb hauv orchestrating autophagickev loj hlobTxawm hais tias nws cov dej ntws qis qis Tbk-1, ncaj qha phosphorylates p62 ntawm Ser-403, ib qho tseem ceeb tseem ceeb rau kev ua haujlwm autophagic ntawm p62 [50]. TBK-1 kuj tseem xav tau rau cytokinesis-induced autophagic tshem tawm cov kab mob, whereas Rab8 knockdown tom qab induction ntawm autophagy ua rau txo qis hauv phagosomes [50].

Daim duab 3 Molecular hloov ntawm GTPase xeev. Me GTPase lub xeev nquag (GTP-bound) yog ua tiav los ntawm nucleotide txauv qhov tseem ceeb uas ua rau kev sib pauv ntawm GDP rau GTP ua rau GTPase ua kom. Active GTPase cuam tshuam nrog ntau yam ntawm cov dej ntws qis los hloov kho lawv cov haujlwm. GTPase activating protein (GAP) inactivates GTP-bound proteins los ntawm boosting lawv cov dej num rau GTP hydrolysis. Daim ntawv GDP-bound tsis tuaj yeem khi cov nyhuv

Nyem qhov no kom tau txais Herbal Cistanche Rau Txhim Kho Kev Paub Txog Kev Ua Haujlwm

Txij li GDP yog nruj me ntsis khi los ntawm Rab GTPases thiab lawv cov intrinsic GTP hydrolysis tus nqi qis txawm tias lawv cov affinity siab 10−1–10−5 μM km [51], Rab GEFs catalyze dissociation ntawm GDP. Rab GAPs pab txhawb lub hydrolysis ntawm GTP. Ob tus neeg tswj hwm yuav tsum tau tswj hwm qhov kev ua haujlwm ib ntus-spatial ntawm Rab GTPases [52]. Cov haujlwm ntawm Rab GTPases, GEFs, thiab GAPs yog qhov tseem ceeb rau kev thauj mus los thiab kev thauj mus los ntawm autophagosomes rau macroautophagy. Macroautophagy xav tau kev tswj hwm nruj, thiab qee qhov Rab GAPs zoo li ua haujlwm hauv kev sib tshooj. Piv txwv li, TBC domain-muaj proteins, TBC1D14 thiab TBC1D15, koom tes endosomal trafficking thiab autophagosome biogenesis. TBC1D5 yog Rab7 GAP uas raug xaiv rau mitochondria los ntawm cov protein FIS1 los tuav Rab7 GTP hydrolysis, uas tseem tuaj yeem mitochondria los tswj kev sib cuag untethering nrog lysosomes [53]. Txij li thaum mitochondria-lysosome kev sib cuag cim cov chaw ntawm Drp1-cov xwm txheej zoo mitochondrial fission, kev hloov pauv hauv Rab7 GTP hydrolysis ua rau ob qho tib si txawv txav lysosomal morphology thiab txo qis ntawm mitochondrial motility [53]. TBC1D2, uas cuam tshuam rau Rab7 GTPase thiab modu lates autophagosome-lysosome fusion, tau pom tias tau qhib los ntawm LRRK1 thaum macroautophagy induction [54].

Cov tsev neeg cov protein ntawm me me Rab GTPases tswj cov kev thauj mus los ntawm vesicle thiab xyuas kom muaj kev lag luam ntawm cov vesicles rau lawv cov phiaj xwm tsim nyog. Rab GTPases cuam tshuam nrog efector proteins xws li cargo sorting complexes, motor proteins, thiab tethering yam, uas yuav tsum tau rau vesicle budding, thauj, thiab fusion ntawm ntau yam intracellular organelles. Hauv cov kab mob mammalian, muaj peb hom autophagy: macroautophagy, microautophagy, thiab chaperone-mediated autophagy (CMA) (Fig. 4). Txhua lub subtype muaj cov txheej txheem sib txawv ntawm substrate xa mus rau lysosome; Txawm li cas los xij, qhov tshwm sim yog tib yam rau lawv txhua tus ua tiav hauv kev xa khoom thauj mus rau lysosome rau degradation thiab recycling.

Macroautophagy ntawm mitochondria yog qhov feem ntau kawm thiab feem ntau hu ua mitophagy. Mitophagy signaling yog tswj los ntawm Lub Hom Phiaj ntawm Rapamycin protein complex 1 (TORC1). Tom qab qhov induction ntawm autophagy, ib tug sequestering membrane hu ua phagophore yog tsim (Fig. 4A). Lub phagophore encloses misfolded proteins thiab/los yog dysfunctional organelles kom txog rau thaum nws tiav rau hauv ib lub hnab ntawv autophagosome. Lub autophagosome ces fuses nrog lysosome, hloov lub cytoplasmic cargo rau hydrolysis. Cov organelles nyob rau hauv lub cargo yog degraded rau hauv cov amino acids thiab yooj yim fatty acids thiab carbohydrates rau tso rau hauv lub cytoplasm los ntawm lysosomal / vacuolar membrane permeases thiab rov siv nyob rau hauv biosynthesis [55].

Fig. 4 Hom kab mob autophagy tswj los ntawm GTP A Hauv macroautophagy (mitophagy), ubiquitin (Ub)-labeled proteins nrhiav p62 los cuam tshuam nrog LC3 los tsim autophagosomes. Rab2 koom nrog hauv phagophore tsim, thaum Rab8b thiab Rab9a koom nrog autophagosome maturation. Arl8 yog nyob rau ntawm lysosome membrane thiab chaw ua lag luam lysosomal. B Hauv chaperone-mediated autophagy (CMA), substrate proteins khi rau monomeric daim ntawv ntawm LAMP-2A tom qab lees paub los ntawm KFERQ motif los ntawm cytosolic Hsc70 chaperon complex. Unfolding ntawm tag nrho substrate yog yuav tsum tau rau nws translocation mus rau hauv ib tug multimeric complex nrog LAMP{11}}A. Muaj ob lub pas dej ntawm GFAP nyob rau hauv daim nyias nyias ntawm lysosomes: 1, nyob rau hauv tej yam kev mob uas muaj siab CMA kev ua, GFAP cuam tshuam nrog LAMP-2A kom stabilize lub complex yuav tsum tau rau lub translocation ntawm CMA cargo nyob rau hauv ib tug GTP-raws li; 2, GFAP cuam tshuam nrog EF1, thaum GTP induces tso tawm EF1 los ntawm GFAP inhibiting CMA thiab txhawb lub disassembly ntawm multimeric LAMP-2AC Nyob rau hauv macroautophagy, autophagic cargo yog engulfed los ntawm invaginations ntawm lub lysosomal membrane kom ntes cov ntsiab lus. Nyob rau hauv tag nrho cov ntawm lawv, recycling tshwm sim tom qab lysosomal degradation

CMA (Fig. 4B) tsis siv cov qauv membranous rau sequester cargo tab sis es tsis txhob siv chaperones los txheeb xyuas cargo proteins thiab translocate lawv mus rau lysosomal membrane, thaum microautophagy (Fig. 4C) siv invaginations los yog protrusions ntawm lub lysosomal membrane los ntes thiab xa cov autophagic cargo mus rau lysosomal membrane [56, 57].

Reactive oxygen hom (ROS) ib feem tswj autophagy. Kev tshaib kev nqhis txhawb ROS (tsuas yog H2O2) ntau lawm hauv mitochondria, uas zoo li tsim nyog rau kev tsim autophagosome. Hauv cov poov xab, autophagy tuaj yeem tswj hwm los ntawm ROS ntawm Atg4, los ntawm oxidation-txo ntawm disulfide daim ntawv cog lus ntawm residues Cys338 thiab Cys 394, uas yuav tsum tau ua kom zoo autophagosome biogenesis [58]. Atg4, ib tug redox protease, ua raws li ib tug conjugating enzyme cleavage C-terminus nyob rau hauv immature Atg8 (mammalian homolog LC3) kom nthuav tawm cov conserved glycine residue rau nws txuas ntxiv mus rau phosphatidylethanolamine (PE). Tsis tas li ntawd, Atg4 kuj tseem ua ib qho enzyme deconjugation uas tshem tawm cov amide khi ntawm Atg8 thiab PE, uas tso tawm nws los ntawm daim nyias nyias rau kev rov ua dua tshiab, uas yog qhov tseem ceeb rau cov txheej txheem conjugation tseem ceeb rau autophagy.

Autophagy: GTP txoj cai hauv kev laus thiab AD

Autophagic clearance ntawm puas cellular Cheebtsam los yog aberrant protein aggregates ua ib qho tseem ceeb los tswj cov oxidative kev nyuaj siab uas txuam nrog kev laus thiab AD [59]. Kev lag luam bidirectional mus rau hauv thiab tawm ntawm cov hlwb yuav tsum muaj kev sib koom tes zoo heev. Autophagy ua haujlwm hauv kev koom nrog endocytosis thiab exocytosis, ob qho tib si uas ua rau muaj kev hloov pauv ntawm cov khoom siv hauv lub cev puas ntsoog siv lysosomal fusion thiab digestion. Autophagy suav nrog tagging cov cellular organelles thiab protein aggregates rau degradation, tom qab ntawd los ntawm kev sib dhos ntawm cov qauv autophagic los thauj cov khoom thauj rau fusion nrog lysosomes kom degrade puas cov proteins thiab cov organelles rau rov ua dua cov amino acids thiab lipids los yog pov tseg. Nws yog ib qho tseem ceeb ntawm cov txheej txheem tseem ceeb los tswj cov cellular homeostasis thiab ua haujlwm. Dysregulation ntawm autophagy tau txuas rau kev laus thiab pathological neurodegenerative kab mob suav nrogAlzheimer tus kab mob. Txawm hais tias nws paub zoo tias ATP qib poob qis nrog lub hnub nyoog hauv cov kab mob pathological [60], cov hnub nyoog hloov pauv hauv GTP qib tsis zoo.

Autophagy induction yog nyob ntawm ADP / ATP tshuav nyiaj li cas. Txo qis ATP ntau lawm txhawb AMP-activated protein kinase (AMPK), thiab stimulation ntawm AMPK inactivates mTOR. AMPK nce autophagy tsis tsuas yog indirectly los ntawm inactivation ntawm mTOR tab sis kuj ncaj qha los ntawm phosphorylation ntawm Unc-51-zoo li kinase 1 (Ulk1) uas yog lub hom phiaj molecular ntawm mTOR nyob rau hauv lub autophagic machinery [61].

GTP depletion tuaj yeem cuam tshuam autophagy hauv kev laus thiab AD

Kev soj ntsuam tom qab mortem ntawm AD cov neeg mob qhia tias muaj kev sib txuam ntawm autophagosomes thiab lwm yam lysosomal autophagic vacuoles hauv dystrophic neurites thiab synaptic terminals, uas yog cov cim neuropathological ntawm AD [62]. Upregulation ntawm autophagosomes nyob rau hauv hippocampal CA1 pyramidal neurons muaj feem xyuam rau cov kev hloov hauv kev qhia ntawm autophagy ntsig txog cov noob (ATG3, ATG5, ATG12, ULK1, thiab PIK3C3 / VPS34) thiab cov proteins (LC3B-II thiab LC3B I) thaum ntxov ]. Cov lus tseeb no qhia tias AD yog txuam nrog kev hloov pauv hauv kev lag luam ntawm autophagosomes.

Autophagy dysregulation tshwm sim hauv ob tus neeg mob AD thiab cov qauv tsiaj. Kev sib sau ntau ntawm autophagic vacuoles nyob rau hauv neuronal dendrites tshwm sim hauv PS1 / APP ob chav transgenic nas thiab tshwm sim ua ntej A plaques [64]. Ib yam li ntawd, cov tsis paub qab hau autophagic vesi cles hauv axons tau pom nyob rau hauv hippocampal neurons ntawm AD nas, deb ua ntej synaptic thiab neuronal poob (Cat aldo li al., 2004 [44, 65, 66]. Tau aggregates kuj degraded. los ntawm txoj kev autophagy [67, 68]. Cov tsiaj qus-hom presenilin gene 1 (PS1) ua raws li ligand ntawm v-ATPase V0a1 subunit tswj kev faib cov v-ATPase subunits rau hauv lysosomes rau acidification. Intracellular A khi rau v- ATPase thiab inhibits acidification [69]. Kev hloov pauv hauv PS1 yog li ua rau lub cev tsis muaj zog ntawm autophagy-lysosome degradation system [70]. Qhov tseem ceeb ntawm kev pheej hmoo ntawm AD, Apolipoprotein E4 (ApoE4), kuj tseem ua rau induction ntawm autophagy los ntawm lysosomal to [71] ua rau muaj kev cuam tshuam kev lag luam endolysosomal, cuam tshuam ntawm synaptic homeostasis thiab txo cov amyloid clearance.Zoo li no qhia tau hais tias txoj kev tsis zoo autophagy-lysosome proteolysis yuav muaj lub luag haujlwm rau kev sib sau ntawm cov kab mob pathogenic xws li A thiab tau hauv AD. Ib qho kev hloov pauv ntawm cov noob uas xav tau rau kev tsim autophagosome, Atg7fox / hma liab, hla nrog APP23 transgenic nas, qhia tias kev tsis txaus ntseeg ntawm autophagy tsis txaus txhawb nqa A tsub zuj zuj hauv CA1 thiab cortical pyramidal neurons, nrog rau kev txo qis hauv extracellular A cov quav hniav thiab inhibition. Ib qho kev ua si [72] Qhov kev soj ntsuam no qhia tias kev hloov pauv hauv autophagosome tsim kom tsis txhob muaj kev ua tiav A uas tuaj yeem ua rau muaj kev cuam tshuam tsis zoo hauv soma [27]. Ib qho kev txuam nrog kuj tau pom nyob rau hauv cis- thiab trans ntsej muag ntawm Golgi vesicles nyob rau hauv lub lig Golgi apparatus, qhia tau hais tias lub organelle no kuj yuav ua tau ib tug haumxeeb alterations uas impair rau tsim kom zoo phagophore [73]. Txhawb nqa qhov kev xav no, me me GTPase Rab2 txuas Golgi network rau autophagy pathway machinery [74]. Rab2 koom nrog tsim phagophores los ntawm kev nrhiav neeg ntxiv thiab ua kom Ulk1. Rab2 cuam tshuam nrog Rubcnl thiab Stx17 (ib qho autophagosomal SNARE protein) kom qhia ntxiv txog kev nrhiav neeg ua haujlwm ntawm HOPS complex los pab txhawb autophagosome maturation thiab fusion nrog lysosomes [74].

Lwm tus tswv cuab ntawm Ras superfamily ntawm me me GTPases koom nrog hauv kev tsim cov vesicle yog ADP ribosylation factor (Arf). Arf GTPase feem ntau koom nrog cov txheej txheem budding hauv Golgi complex, kev nrhiav neeg ua haujlwm ntawm lub tsho tiv no thaum lub sij hawm tsim cov vesicle rau cov khoom lag luam membrane. Arf GTPase koom nrog kev tswj hwm APP kev lag luam los ntawm MINTs cov proteins, cov khoom tseem ceeb rau kev sib xyaw ntawm synaptic vesicles. MINT proteins khi ncaj qha rau Arf GTPases thiab sib koom ua ke nrog APP-muaj vesicles rau thaj tsam ntawm Golgi / trans-Golgi network (TGN), nrog rau qib APP intracellular proportional rau MINT qib [75]. Lub knockdown ntawm Arf1 txo qis qhov tso tawm ntawm amyloid peptides [76], qhia txog qhov cuam tshuam ntawm kev ua tsis tiav hauv Arf1 kev ua haujlwm ntawm kev lag luam ntawm APP, uas tuaj yeem sib sau ua ke hauv intracellular tsub zuj zuj (Daim duab 5).

Dysregulation ntawm ntau yam Rab proteins kuj pab txhawb rau AD pathology. Rab1 dysregulation induces fragmentation ntawm Golgi apparatus, uas ua rau hyperphosphorylation ntawm tau los ntawm kev ua kom cdk5 thiab ERK1/2 [77, 78]. Qhov tsis xws luag hauv Rab6 tuaj yeem cuam tshuam rau kev zais ntawm APP rau hauv

Fig. 5 Autophagy yuav tsum muaj kev koom tes ntawm ob peb GTPases me. Nyob rau theem pib, Rab2 nrhiav thiab qhib ULK1 hauv kev tsim phagophore, thaum Rab9a thiab Rab8b koom nrog hauv autophagosome maturation. Arf koom nrog hauv budding nyob rau hauv lub Golgi complex, thiab recruitment ntawm lub tsho tiv no proteins thaum lub sij hawm tsim vesicle. Rab1 koom nrog hauv kev thauj mus los ntawm ob txoj kev vesicular ntawm endoplasmic reticulum (ER) thiab Golgi apparatus. Sar1 GTPase koom nrog hauv kev thauj mus los ntawm COPII raws li txoj kev tawm ntawm APP thaum nws qhov kev sib haum xeeb kawg tau mus txog. Rab6 nyob hauv TGN thiab koom nrog kev thauj mus los ntawm Golgi mus rau ER, thiab tau cuam tshuam nrog kev tswj hwm ntawm vesicular thauj thiab kev ua haujlwm ntawm APP. Rab11 tswj cov endosome recycling rau plasma membrane. Kev cuam tshuam hauv vesicular export uas muaj APP-BACE tuaj yeem ua rau muaj kev cuam tshuam ntawm exosomes. Arl8 tswj cov kev thauj mus los thiab lysosomal fusion ntawm microtubules raws li nruab nrab ntawm cov neuron, ua rau muaj kev hloov pauv hauv tus nqi zais cia, uas tuaj yeem txhawb kev hloov pauv hauv anterograde kev lag luam ntawm APP uas ua rau muaj kev cuam tshuam hauv lub cev. Txhawb nqa intracellular tsub zuj zuj, ib qho exome sequencing tsom xam pom Rab11A/B raws li ib feem ntawm lig-pib pib AD txaus ntshai. Rab11 tswj cov endosome recycling rau plasma membrane. Silencing Rab11A/B hauv thawj cov neurons cais los ntawm APP transgenic nas txo qis A qib hauv cov supernatants sau thiab txheeb xyuas los ntawm electrochemiluminescence (ECL) [79]. Cov ntaub ntawv no qhia tau hais tias qhov tsub zuj zuj ntawm A kuj tuaj yeem tsim los ntawm kev ua tsis tiav hauv kev xa tawm ntawm APP-muaj vesicles, uas tuaj yeem muab txoj hauv kev rau cleavage los ntawm secretase hauv vesicular membrane [27] (Fig. 1B). Txij li thaum tsim cov APP-muaj vesicles thiab tsim ntawm phagophore koom nrog kev ua haujlwm raug ntawm ER-Golgi uas tau tsav los ntawm GTPases me me, qhov tsis txaus ntawm GTP yuav ua rau muaj kev cuam tshuam hauv ntim ntawm APP uas tuaj yeem cuam tshuam nws qhov zais cia thiab txhawb kev sib txuam hauv cov cell. .

Cov kev sib raug zoo ntawm autophagy mus rau tsub zuj zuj ntawm intracellular A yog txhawb los ntawm lub hnub nyoog-hais txog colocalization teeb liab ntawm p62- qhia kev tsim ntawm autophagosome thiab A cov ntaub ntawv pom nyob rau hauv thawj kab lis kev cai hippocampal neurons los ntawm cov laus 3xTg-AD nas [27] thiab nyob rau hauv APP23-cov nas hloov pauv nrog Atg7 foxed nas [73]. Lwm qhov tseeb nthuav yog tias tsis muaj cov teeb liab ntawm kev sib sau ua ke hauv autophagy los zoo rau cathepsin D [27]. Cov ntaub ntawv no yuav qhia tau tias kev ua haujlwm tsis zoo hauv cov kauj ruam ua ntej hauv autophagy lossis hauv lysosomal muaj nuj nqi hauv AD qauv neurons (Fig. 6) [26].

GTP txoj cai hauv CMA hauv AD

Hloov cov organelles, CMA degrades me me molecules nyob rau hauv eukaryotic hlwb induced los ntawm ntev kev tshaib kev nqhis los yog me ntsis oxidative kev nyuaj siab. CMA tau thov kom tswj hwm los ntawm GTP qib [80]. Cov kev cai no suav nrog kev koom tes ntawm intermediate filament glial fibrillary acidic protein (GFAP) thiab elongation factor-1 alpha (EF1) [46, 81]. GFAP muaj nyob rau hauv ob lub pas dej sib txawv ntawm lub lysosomal membrane, ib feem khi rau LAMP-2A thiab lwm daim ntawv tsis muaj kev cuam tshuam nrog EF1 . Peb lub KFERQ motifs hauv Hsc70 chaperon coj nws mus rau lysosomal daim nyias nyias uas nws cuam tshuam nrog protein complex LAMP-2A thiab stabilizes translocation ntawm CMA cargo mus rau hauv lub lysosomal lumen. Ib feem ntawm GFAP tsis khi rau LAMP-2Ib pab txhawb rau GTP txoj cai. Nyob rau hauv lub xub ntiag ntawm GTP, EF1 yog tso tawm los ntawm GFAP ntawm lub lysosomal membrane uas txhawb kev dissociation ntawm GFAP thiab LAMP-2A, mobilizing LAMP-2A mus rau lipid microdomains rau nws degradation thiab tom qab CMA inhibition [ 81] ib. Tsis ua haujlwm hauv teeb ntsia ntawm lub lysosomal membrane kuj tseem cuam tshuam nrog kev laus, uas tseem ua rau txo qis hauv CMA haujlwm [82] (Daim duab 4B)

Tseem muaj lwm daim ntawv ntawm mammalian autophagosome biogenesis ua haujlwm los ntawm ib qho enigmatic non-canon ical VPS 34- txoj kev ywj pheej. Phosphoinositides (PIs) txhais cov txheej txheem ntawm daim nyias nyias thiab tswj tau ntau yam kev lag luam membrane. Phosphatidylinositol 5-kinase (PIKfyve) converts endosome-localized phosphatidylinositol -3-phosphate (PI(3)P) rau PI(3,5) P2, ib qho tseem ceeb regulator ntawm ntxov mus rau lig endosome membrane kev lag luam [83] . Tsis tas li ntawd, PIKfyve complex tseem yog lub luag haujlwm rau kev tsim cov PI (5)P los ntawm PIs thiab tswj kev tsim autophagosome. PI(5) P tswj autophagy ntawm PI(3)P effectors (nrhiav WIPI2 thiab DFCP1 cov proteins), uas muab cov txheej txheem txheej txheem rau lwm txoj hauv kev autophagy. PI(5)P yog siv los ntawm phosphatidylinositol 5-phosphate 4-kinase (PI5P4K) uas tswj PI(5)P qib siv GTP es tsis yog ATP rau PI(5)P phosphorylation kom tau PI(4, 5) P2 raws li cov khoom kawg uas tswj cov actin cytoskeleton remodeling [84]. Lawv pom PI (3,5) P2 muaj qhov tsis sib xws rau cofilin, uas disassembles actin filaments, thiab muaj affinity siab rau N-WASP, uas ua rau Arp2/3 complex los pib actin nucleation los thauj endocytic vesicles los ntawm plasma membrane. PI5P4K kev ua ub no tau npaj kom muaj kev cuam tshuam txog kev hloov pauv ncaj qha rau lub cev muaj zog GTP concentration, ua raws li cov khoom siv hauv cellular GTP-sensor [85]. Hauv cov hlwb uas tsis muaj PI3P (qis PI (3,5) P2) nrog kaw VPS34, PIKfyve complex sustains autophagy los ntawm kev siv PI5P [85]. Cov ntaub ntawv no qhia tias PIKfyve muaj lub luag haujlwm tseem ceeb hauv kev hloov kho ntawm autophagy. Kev ua haujlwm tsis zoo PIKfyve tsav cov tsim ntawm cov vacuoles o, pom tau yooj yim ntawm qhov tsis tshua muaj nyob hauv cov hlwb [86]. Lub intra-cellular domain ntawm APP khi Vac14 subunit ntawm PIKfyve complex, cuam tshuam PI (3,5) P2 ntau lawm [87]. PI(3,5)P2 khi thiab qhib lub endolysosomal TRPML channel [88]. Lawv pom cov vacuoles loj hauv PI(3,5) P2-cov nas fibroblasts tsis txaus uas tau raug tshem tawm los ntawm kev noj qab haus huv TRPML1 channel. TRPML conductivity thiab lysosomal acidification raug cuam tshuam [89].

Kev vam meej ntawm mitochondrial fission thiab fusion ntawm GTP

Ntxiv rau kev muab ATP los ntawm oxidative phosphorylation, mitochondria kuj muab GTP los ntawm NME4 thiab nws cov nucleoside diphosphate kinase kev ua haujlwm [8]. Qhov no mitochondrial mov ntawm lub zog yog qhov tseem ceeb rau tiam ntawm synaptic vesicles rau tso tawm ntawm axon terminals thiab rau vesicular recycling ntawm synapses. Synaptic poob hauv AD tuaj yeem tshwm sim los ntawm kev poob ntawm bioenergetic peev xwm los tswj cov txheej txheem tseem ceeb no. Yog li, tus naj npawb thiab thaj chaw ntawm mitochondria rau synapses yuav txiav txim siab lub zog muaj peev xwm rau endocytosis thiab exocytosis. Mitochondrial dynamics delicately sib npaug fission thiab fusion tswj los ntawm Drp1 thiab Fis1, Mf1, Mfn2, thiab Opa1 [90, 91] (Fig. 7). Kev hloov pauv ATP rau GTP yog tswj hwm hauv zos los ntawm thaj chaw nucleoside diphosphate kinases (NDPKs) los ntawm NME noob 1-4 [51]. NME1 thiab 2 (qee zaus hu ua NM23 H1 thiab H2) feem ntau yog cytosolic, thaum NME3 thiab 4 (NM23 H3, H4) yog mitochondrial. Lub mitochondrial NDPKs complex nrog tshwj xeeb dynamin GTPases rau channel GTP ncaj qha los ntawm ATP hydrolysis [16]. Qhov sib npaug ntawm mitochondria fission thiab fusion yog rhiab rau redox imbalance. Ob qho endogenous lossis exogenous daim ntawv thov ntawm ROS activates mitochondrial fission, inducing mitochondrial fragmentation thiab tom qab mitochondrial dysfunction [90]. Qhov no ua rau ROS ntau dhau thiab lub voj voog tsis zoo uas ua rau muaj kev ntxhov siab oxidative thiab thaum kawg ua rau oxidative tsis txaus hauv AD [92]. Fission yog tswj los ntawm dynamin GTPases Drp1 thiab Fis1 nrog Km nyob ib ncig ntawm 100 μM [51]. Lawv polymerize thiab constrict tubular daim nyias nyias zoo li endocytosis. Fis1 yog nyob rau hauv lub mitochondrial membrane sab nrauv [90, 93, 94].

Daim duab 7 GTP-dependent mitochondrial dynamic morphology ntawm fission thiab fusion. Sab laug fusion vaj huam sib luag: Dynamin-related protein-1 (Drp1) executes mitochondrial fission los ntawm nws tus kheej-polymerizing nyob ib ncig ntawm lub mitochondrial membrane constricting thiab severing ob daim nyias nyias nyob rau hauv ib tug txheej txheem nyob ntawm GTP hydrolysis. Txoj cai fusion vaj huam sib luag: Mitofusin-1 thiab -2 (MTF1/2) tether lub sab nraud mitochondrial membranes uas nyob ib sab nyob rau hauv ib tug txheej txheem nyob ntawm GTP hydrolysis. OPA1 ua rau sab hauv mitochondria membrane fusion siv GTP hauv zos muab los ntawm NME4. Liab dashed xub qhia qhov kev hloov ntawm lub organelle.

Fusion yog tswj los ntawm peb GTPase proteins: Opa1, nyob rau hauv lub puab mitochondria membrane, thiab Mfn1 thiab Mfn2, nyob rau hauv lub sab nrauv mitochondrial membrane. Opa1 GTPase nrog ib Km nyob ib ncig ntawm 500 μM yuav tsum muaj ntau theem ntawm GTP rau polymerize thiab mechanize mitochondrial membrane fusion rau hauv cov hlab [51].

hypoxia, lub zog muaj zog, thiab nce oxidized redox xeev. Nce oxidative kev nyuaj siab thiab nce ROS theem ua rau fragmentation ntawm mitochondria thiab induction ntawm DRP1 fission-dependent mitophagy nyob rau hauv nas thiab HeLa hlwb. Qhov no tsis ua rau kev tuag ntawm tes thiab autophagy vim tias theem nrab ntawm ROS tsis txaus los ua rau tsis muaj kev xaiv autophagy [95]. Qhov tseeb, qhov mitophagy no tuaj yeem cuam tshuam los ntawm N-acetyl-l-cysteine ​​los ntawm kev siv lub pas dej glutathione thiab ua tau rau ntawm Atg4. Kev txo qis hauv lub pas dej glutathione kuj ua rau mitophagy tab sis tsis yog autophagy. Hloov pauv, qhov sib ntxiv ntawm daim ntawv cell-permeable ntawm glutathione inhibited mitophagy [96]. Yog li, lub xeev oxidative redox txhawb lub hom phiaj-xaiv tiv thaiv kev tshem tawm ntawm mitochondria dysfunctional. Qhov no kuj qhia txog kev sib koom ua ke ntawm redox tshuav nyiaj li cas thiab qib zog kom ua kom muaj kev noj qab haus huv mitochondrial muaj nuj nqi thiab tswj kev hloov pauv ntawm cov mitochondria puas.

Kev puas tsuaj hauv fusion thiab fission tau cuam tshuam hauv AD. Hauv tus qauv nas, A cuam tshuam nrog fs sion protein Drp1, nrog rau kev nce ntxiv hauv cov dawb radical ntau lawm, uas txuas ntxiv ua rau Drp1 thiab Fis1, ua rau ntau dhau mitochondria fragmentation, kev thauj mus los ntawm mitochondria mus rau synapses, qis ers synaptic ATP, thiab thaum kawg ua rau. Synaptic tsis ua haujlwm [97] p-tau kuj cuam tshuam nrog Drp1 thiab txhim kho GTPase Drp1 enzymatic kev ua haujlwm, ua rau muaj kev tawg ntau ntawm mitochondria thiab mitochondrial dysfunction hauv AD [98]. Ib qho Drp1 S-nitrosylation adduct (SNO-Drp1), ntxiv dag zog rau nws cov haujlwm thiab ua rau ntau dhau mitochondrial fragmentation, thiab synapse poob [99].

Impaired lysosomal muaj nuj nqi hauv AD tshwm sim los ntawm hnub nyoog txog lub zog depletion

Lysosomal digestion ntawm autophagic cargo yog cov kauj ruam kawg rau kev ua tiav ntawm autophagy. Yog li ntawd, lysosomes yuav tsum tswj lawv cov acidic milieu rau pH-raws li degradation ntawm cargo los ntawm acid-activated peptidases, lipases, nucleases, thiab glycosidases. Rau lysosomal acidification, influx ntawm protons yog ua los ntawm ob qho tib si v-ATPase, ATP-raws li proton twj tso kua mis, thiab chloride proton antiporters, thaum cation efflux yog kho los ntawm transporters TPC thiab TRPML, uas kuj koom nyob rau hauv lub pH tshuav nyiaj li cas [ 100]. Presenilin-1 (PS1) tswj kev faib cov v-ATPase subunits rau hauv lysosomes ua lub ligand ntawm v-ATPase V0a1 subunit thiab tswj lysosomal homeostasis ntawm TRPML1 [69]. PS1 kev hloov pauv tau txuas rau qis lysosomal acidification, dysregulation ntawm autophagy-lysosome degradation system, thiab pathogenesis ntawm qhov pib AD [26].

Arl8 (ib qho Arf-zoo li G protein) yog GTPase me me nyob rau ntawm lysosomes uas ua raws li kev sib txuas ntawm lysosomes thiab kinesin -1 los pab txhawb lysosomal traf fcking raws axons (Fig. 8B) [101]. Arl8b kuj ua raws li kev hloov pauv los tswj kev koom tes ntawm HOPS complex nrog lysosomal membrane [102]. Kev cuam tshuam ntawm Arl8b muaj nuj nqi ua rau muaj qhov txawv txav ntawm cov roj cholesterol nyob rau hauv daim nyias nyias ntawm lysosomes tsav tsheb tsis zoo axonal lysosome kev lag luam thiab ua rau autophagic kev nyuaj siab thiab axonal autophagosome tsub zuj zuj [103]. Tsis tas li ntawd, nce Arl8b qhia tau cawm lysosome thauj mus rau hauv axons thiab autophagic stress. Overexpression ntawm Arl8 kuj txhawb lub bidirectional motility ntawm lysosomes ntawm microtubules los ntawm kev khi rau kinesin -1 linker SKIP los txuas kine kev txhaum thiab lub zog motility [104]. SKIP xav tau Arl8 hauv nws txoj haujlwm GTP-khoom lub xeev rau kev khi. Txawm li cas los xij, overexpression ntawm Arl8b kuj ua rau muaj kev tawm tsam alkalinization ntawm lysosomes thiab txav mus rau lub cell periphery piv rau ib qho kev faib tawm ntau dua ntawm lysosomes thoob plaws hauv cytoplasm [105]. Ib txoj kev tshawb fawb proteomic hauv tib neeg cov ntaub so ntswg tau tshaj tawm txog kev txhawb nqa ntawm Arl8b hauv amyloid plaques [106]. Cov ntaub ntawv no qhia tias kev hloov pauv hauv kev qhia lossis kev ua haujlwm ntawm Arl8 cuam tshuam rau fusion ntawm lysosome nrog autophagy lossis lig endosome, uas tuaj yeem cuam tshuam rau hauv autophagosome tsub zuj zuj hauv AD. Txij li thaum tsim cov vesicles secretory xa mus rau plasma membrane yog GTP-raws li txheej txheem, xav tau Arf thiab Rab GTPases, qhov tsis xws luag hauv GTP qib yuav cuam tshuam rau kev lag luam vesicular.

Lysosome biogenesis yog tswj hwm los ntawm mTORC1 thiab qhov kev hloov pauv hloov pauv EB (TFEB) tsim kom muaj kev rov qab hloov pauv ntawm qhov chaw lysosome. mTORC1 phosphorylates TFEB ntawm Ser211, tsav tsheb yog li ua rau TFEB thauj mus rau lub nucleus los txhim kho v-ATPase kev qhia thiab lwm cov noob koom nrog hauv lysosome biogenesis thiab autophagosome tsim [107, 108]. Qhov sib ntxiv ntawm A rau microglial hlwb txo TFEB nyob rau hauv lub nucleus thiab impairs kev ua ntawm A [109]. Cov kev cai no los ntawm mTORC1 yog nyob rau hauv lem txhawb los ntawm me me GTPases nrog rau Rheb thiab Rag, amino acid-sensing Cheebtsam muaj nyob rau hauv lub multiprotein signaling complex regulator uas ua raws li ib tug activator ntawm mTORC1 [110]. Txij li thaum lysosomal acidification yuav tsum tau ATP rau V-ATPase muaj nuj nqi thiab GTP rau GTPase-mediated kev cai ntawm TORC1, peb xav hais tias lub zog depletion vim kev laus los yog AD-zoo li pathological tej yam kev mob ncaj qha impairs lysosomal muaj nuj nqi. Tsis tas li ntawd, kev txiav txim siab tias lysosomal acidification cuam tshuam nrog kev noj zaub mov noj-kho kev tswj hwm kev sib cuam tshuam ntawm v-ATPase thiab TORC1 ntawm TFEB, lub voj voog ntawm kev yoo mov thiab kev noj zaub mov tuaj yeem muaj txiaj ntsig lysosomal kev ua haujlwm hauv AD [111], thaum noj cov suab thaj ntau zaus tuaj yeem ua rau tsis zoo. Impaired lysosomes tuaj yeem ua rau autophagosomes tag nrho ntawm puas mitochondria thiab enriched nrog A -aggregates tsis muaj peev xwm degraded. Txij li thaum autophagy nqa tawm qhov hloov pauv ntawm cov kab mob uas raug puas los yog hnub nyoog, nws cov kev saib xyuas raug cuam tshuam los ntawm kev hloov pauv metabolic vim muaj hnub nyoog. Cov hnub nyoog cuam tshuam txog kev hloov pauv hauv metabolic thiab tsis muaj lysosomes tuaj yeem ua rau muaj kev cuam tshuam ntawm metabolic hloov xws li lub zog depletion thiab / lossis oxidative redox hloov yog li, GTP qib tuaj yeem qis dua hauv kev ua neej nyob qis qis, uas yuav ua rau txoj hauv kev tsis zoo ntawm GTP-dependent. protein degradation nrog lub hnub nyoog nce qib. Cov kev soj ntsuam no qhia tau hais tias muaj kev sib raug zoo ntawm kev hloov pauv hauv txoj kev loj hlob ntawm autophagosome thiab metabolic tsis txaus uas tshwm sim nrog kev loj hlob ntawm tus kab mob thiab kev laus. Tsis tas li ntawd, aberrant A tsub zuj zuj tuaj yeem yog qhov tshwm sim ntawm cov dej ntws tsis zoo hauv GTP uas cuam tshuam kev ua haujlwm ntawm autophagic ntawm A thiab tau, tej zaum ua ntej tshaj qhov sib sau ntawm amyloid secretion, o, thiab cov quav hniav buildup.

Daim duab 8 Dynamic instability ntawm microtubules txuam nrog GTP. GTP molecules khi rau E-site thiab N-site ntawm / heterodimer tubulins. GTP ntawm E-site yog hydrolyzed los ua GDP- -tubulin thiab pauv rau GTP-bound heterodimer tshiab / los sib sau ua ke subunits. Heterodimers tau ntxiv rau qhov loj hlob microtubule lattice rau polymerization tsim ib txheej tshiab ntawm GTP-heterodimers hu ua GTP-cap. Depolymerization tshwm sim thaum heterodimers tawm ntawm qhov shrinking microtubule lattice. Hyperphosphorylation ntawm microtubule-txuas nrog cov protein, tau txhawb nqa neurofibrillary tangle (NFT) tsim thiab microtubule destabilization. Kev hloov ntawm lub xeev loj hlob mus rau lub xeev kev puas tsuaj loj zuj zus. B Endolysosome tsim yuav tsum tau lysosomes txav raws microtubule lem nyob rau hauv txoj kev zoo, thaum lig endosomes txav mus rau qhov tsis zoo. Lub lysosomal multiprotein complex BORC (tsis pom) ua kom lub me me GTPase Arl8 los koom nrog kinesin-tsav ntxiv-kawg thauj. Rau kev tshem tawm-kawg thauj, Rab7- GTP-txheej xeev lub xeev recruits Rab-interacting lysosomal protein (RILP) thiab cytosolic oxysterol-binding protein-related protein 1 (ORP1L) tsim cov dynein-dynactin complex. NFT tsim cuam tshuam vesicular tsheb khiav raws microtubules.

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