Macroautophagy Thiab Mitophagy nyob rau hauv Neurodegenerative Disorders: Tsom Rau Kev Kho Mob Ntu 1

Abstract:

Macroautophagy, ib qho kev tswj xyuas zoo, yog ib txoj hauv kev txuag kev hloov pauv ntawm lysosomal degradation ntawm cov protein aggregates, kab mob, thiab puas organelles.

Protein yog ib qho ntawm cov khoom noj uas xav tau los ntawm tib neeg lub cev. Nws tsis yog tsuas yog ib qho tseem ceeb ntawm lub cev muaj pes tsawg leeg tab sis kuj tseem cuam tshuam nrog kev loj hlob ntawm lub hlwb thiab kev txawj ntse. Protein ua lub luag haujlwm tseem ceeb hauv lub hlwb. Nws tsis tsuas yog pab tsim thiab kho cov hlwb hlwb tab sis kuj pab lub hlwb txoj kev kawm thiab kev nco.

Protein yog ib qho tseem ceeb ntawm cov hlwb hlwb. Nws tuaj yeem pab kev loj hlob thiab kho cov hlwb, txhawb kev sib txuas thiab kev sib txuas lus ntawm cov neurons, thiab yog li pab tib neeg ntxiv dag zog rau lawv lub cim xeeb. Tsis tas li ntawd, cov protein kuj tuaj yeem tsim qee yam tseem ceeb xws li neurotransmitters, uas ua lub luag haujlwm hauv kev xa cov ntaub ntawv hauv lub hlwb thiab pab txhim kho lub hlwb.

Los ntawm cov khoom noj khoom haus, cov khoom noj uas muaj protein ntau muaj xws li nqaij, ntses, qe, taum, thiab lwm yam. Thaum tib neeg noj cov protein txaus, lawv tuaj yeem tau txais cov khoom noj khoom haus txaus rau lub hlwb, yog li txhawb kev loj hlob ntawm lub hlwb, txhim kho kev txawj ntse. , thiab pab tib neeg kawm thiab nco tau zoo dua.

Nyob rau tib lub sijhawm, rau cov protein kom ua tiav nws lub luag haujlwm, tib neeg kuj yuav tsum tswj hwm qhov sib npaug ntawm lawv cov zaub mov, noj txiv hmab txiv ntoo thiab zaub ntau, tsis txhob noj cov zaub mov muaj roj ntau thiab ntsev ntau, thiab tswj kev noj qab haus huv thiab kev xav. , txhawm rau ua kom cov haujlwm ntawm cov protein ntau hauv lub hlwb.

Yog li ntawd, peb tuaj yeem xaus tias cov protein muaj feem cuam tshuam nrog kev nco. Kev noj cov protein ntau tsis yog tsuas yog muaj txiaj ntsig zoo rau lub cev noj qab haus huv xwb tab sis kuj tuaj yeem txhawb tib neeg kom kawm thiab nco qab zoo dua, ntxiv ntau xim rau peb lub neej. Nws pom tau tias peb yuav tsum txhim kho kev nco. Cistanche tuaj yeem txhim kho kev nco zoo vim Cistanche muaj cov tshuaj tiv thaiv antioxidant, tiv thaiv kab mob, thiab tiv thaiv kev laus, uas tuaj yeem pab txo qis oxidation thiab inflammatory tshwm sim hauv lub hlwb, yog li tiv thaiv kev noj qab haus huv ntawm lub paj hlwb. Tsis tas li ntawd, Cistanche tseem tuaj yeem txhawb kev loj hlob thiab kho cov paj hlwb, yog li txhim kho kev sib txuas thiab kev ua haujlwm ntawm neural networks. Cov teebmeem no tuaj yeem pab txhim kho kev nco, kev kawm muaj peev xwm, thiab kev xav nrawm, thiab tseem tuaj yeem tiv thaiv qhov tshwm sim ntawm kev paub tsis meej thiab cov kab mob neurodegenerative.

Nyem paub txoj hauv kev los txhim kho lub hlwb

Raws li ib feem ntawm nws lub luag haujlwm tseem ceeb hauv homeostatic, macroautophagy deregulation yog txuam nrog ntau yam kev mob ntawm tib neeg, nrog rau cov kab mob neurodegenerative. Muaj ntau cov ntaub ntawv pov thawj uas koom nrog cov protein misfolding thiab mitochondrial dysfunction hauv etiology ntawm Alzheimer's, Parkinson's, thiab Huntington'sdiseases.

Macroautophagy tau cuam tshuam rau kev degradation ntawm cov protein sib txawv xws li A , tau , alpha-synuclein ( -syn ), thiab mutant huntingtin (mHtt ) thiab hauv kev tshem tawm ntawm kev ua haujlwm tsis zoo ntawm mitochondria.

Ua raws li cov kev xav no, lub hom phiaj ntawm autophagy tuaj yeem sawv cev rau cov tswv yim kho mob kom tshem tawm cov protein sib sau ua ke thiab txhim kho mitochondrialfunction hauv cov teeb meem no.

Kev tshuaj xyuas tam sim no piav qhia txog peb qhov kev nkag siab tam sim no ntawm lub luag haujlwm ntawm macroautophagy hauv cov kab mob neurodegenerative thiab tsom mus rau cov tswv yim ua tau rau nws txoj kev kho mob.

Ntsiab lus: neurodegenerative mob; autophagy; mitophagy mitochondrial tsis ua haujlwm; mutantproteins; cov tswv yim kho mob.

1. Txheej txheem cej luam ntawm Autophagy

Autophagy yog ib qho tseem ceeb ntawm cov txheej txheem intracellular tus kheej-degradative uas tswj intracellular homeostasis los ntawm degradation thiab recycling ntawm tshuaj lom macromolecules thiab puas organelles [1].

Ntau qhov kev paub tam sim no txog autophagy tau pom nyob rau hauv cov qauv polarized lossis tsis-polarized hlwb [2]. Cov txheej txheem no tshwm sim ntawm qib basal nyob rau hauv yuav luag tag nrho cov mammalian hlwb thiab muaj peev xwm txhawb tau nyob rau hauv teb rau kev tshaib kev nqhis, muab lub cell nrog lub tsev blocks rau tshiab proteins thiab lipids. Autophagy plays ib qho tseem ceeb luag hauj lwm nyob rau hauv lub clearance ntawm protein aggregates thiab pathogens thiab kev tswj ntawm inflammatory thiab tiv thaiv kab mob [3,4].

Rau cov laj thawj no, deregulation ntawm autophagy tau cuam tshuam rau ntau yam kab mob, nrog rau cov kab mob neurodegenerative. Autophagyassumes lub luag haujlwm tseem ceeb hauv cov neurons vim tias cov hlwb no muaj kev nkag siab zoo rau kev sib sau ntawm cov misfolded proteins.

Neurons cia siab rau anterograde thiab retrograde thauj mus los daws cov kev xav tau ntawm metabolic thiab yog li tsim cov aggregates tsis tsuas yog tshem tawm cov haujlwm tsis raug ntawm cov neurons tab sis kuj cuam tshuam nrog kev sib txuas lus nrog ib puag ncig ib puag ncig.

Yog li ntawd, kev sib cuam tshuam ntawm autophagy thiab neurodegeneration yuav tsum muaj kev nkag siab zoo ntawm txoj kev tswj hwm thiab ntau cov kauj ruam uas koom nrog hauv txhua txoj kev.

Autophagy tuaj yeem muab faib ua peb hom tseem ceeb, raws li kev xa khoom ntawm cargoto lysosome: macroautophagy, microautophagy, thiab chaperone-mediated autophagy (CMA). Hauv macroautophagy, cytoplasmic cargo yog engulfed los ntawm kev loj hlob ob-membrane vesicle uas, tom qab kaw (autophagosome), fuses nrog lysosome rau degradation (autolysosome) [5].

Cov txheej txheem yog complex thiab koom nrog ib pab pawg neeg ntawm cov proteins uas muaj feem xyuam rau autophagy ua nyob rau hauv ib tug concerted flux, thiab nws yuav tshwm sim randomly (bulkmacroautophagy) los yog xaiv los ntawm tej adaptors. Hauv microautophagy, cov khoom thauj (feem ntau yog cov proteins) ncaj qha los ntawm kev nkag mus ntawm lysosome membranes thiab endosomal vesicles [6].

CMA yog cov txheej txheem xaiv los ntawm cov proteins uas muaj lub hom phiaj tshwj xeeb (pentapeptide KFERQ motif) tau lees paub los ntawm cytosolic chaperoneheat poob siab cognate 70 (Hsc70) thiab nws cov co-chaperones, pab kev hloov pauv ntawm cargointo lub lumen ntawm lysosomes los ntawm lysosomal membrane. 2A receptor (LAMP2A) [7].

CMA suav nrog lwm txoj hauv kev lysosome-mediated degradation txoj hauv kev uas tuaj yeem hloov kho thaum muaj kev cuam tshuam ntawm macroautophagy tshwm sim [8]. Rau qhov ntsuas ntawm qhov kev tshuaj xyuas no, macroautophagy thiab xaiv autophagy ntawm mitochondria, hu ua mitophagy, yuav tau piav qhia ntxiv thiab tshawb nrhiav hauv cov ntsiab lus ntawm kev ua haujlwm neuronal thiab neurodegeneration (Daim duab 1).

1.1. Macroautophagy

Macroautophagy yog txheej txheem nyuaj thiab ua ntu zus pib nrog autophagosomeformation thiab engulfment ntawm cargo, ua raws li los ntawm kev kaw thiab maturation, thiab thaum kawg fusion nrog lysosome rau degradation. Txhua yam ntawm cov kauj ruam no suav nrog qhov sib txawv ntawm autophagy-related (ATG) cov proteins uas ua haujlwm sib koom ua ke autophagic flux nrog autophagosomebiogenesis thiab fusion nrog lysosome [9].

Kev pib ntawm autophagy yog tswj hwm los ntawm cov xwm txheej phosphorylation ntawm unc-51-zoo li autophagy activating kinase 1 (ULK1), uas tswj hwm los ntawm cov kab mob siab tshaj plaws ntawm lub hom phiaj ntawm rapamycin complex 1 (mTORC1) [10].mTORC1 muaj cov khoom noj muaj txiaj ntsig zoo. Cov xwm txheej lossis thaum txoj kev PI3K/Akt raug txhawb los ntawm kev loj hlob (xws li insulin-zoo li kev loj hlob zoo li -1, IGF1).

Active mTORC1 phosphorylates ULK1 thiab ATG13, cov khoom ntawm ULK1 pib ua haujlwm (tseem tsim los ntawm ATG101 thiab FAK tsev neeg kinase-interacting protein nrog 200 kDa, FIP200) [11] suppressing autophagy. Hauv cov xwm txheej tsis txaus, mTORC1 yog inactivated, ua rau ULK1autophosphorylation [12].

Ntxiv mus, thaum lub cev muaj zog ntawm tes tsis tshua muaj zog, AMP ua rau AMPK, uas nyob rau hauv lem inhibits mTORC1 thiab phosphorylates ULK1, txhawb autophagy [12,13]. Thaum ULK1 qhib, nws phosphorylates ATG13 thiab FIP200, yog li ua kom tag nrho ULK1 pib ua haujlwm [14].

Tom qab ULK1 txoj haujlwm ua haujlwm, nws hloov mus rau omegasomes (cov cheeb tsam tshwj xeeb ntawm endoplasmic reticulum (ER), pib phagophore membrane sib dhos rau autophagosome biogenesis [15].

Ntawm omegasomes, ULK1 txhawb nqa kev nrhiav neeg ua haujlwm thiab ua kom cov chav kawm III phosphatidylinositol 3-kinasecomplex (PI3PK, tsim los ntawm vacuolar protein sorting 34, beclin-1, phosphoinositide-3-kinase regulatory subunit 14L, thiab los ntawm phosphorylation ntawm Beclin-1 [15,16].PI3PK yog lub luag haujlwm rau tiam ntawm phosphatidylinositol-3 phosphate (PI3P) forphagophore expansion [17].

Thawj qhov chaw ntawm daim nyias nyias rau phagophore nucleation suav nrog COPII vesicles, ATG9 vesicle reservoirs, thiab ER-omegasome membrane nws tus kheej [18]. ATG9 yog transmembrane glycoprotein uas ncig ntawm trans-Golgi network (TGN) thiab endosomalsystem los ntawm kev rov ua dua endosomes [19] thiab raug xaiv rau omegasome thaum autophagyinduction, yog li xa cov membranes mus rau nascent phagophore [20,21].

Ntxiv mus, ATG9 xa mus rau thiab los ntawm cov plasma membrane, tom kawg los ntawm cov txheej txheem clathrin-mediated [22]. Kev lag luam ntawm ATG9 ntawm daim nyias nyias yog nyob ntawm ULK1-mediatedphosphorylation hauv basal thiab autophagy-inducing mob [23]. Lwm cov khoom siv hauv daim nyias nyias, xws li mitochondria, Golgi complex, thiab plasma membrane, kuj tau raug npaj los koom rau hauv lub vesicle nucleation thiab expansion [24–26].

Tshwj xeeb solubleN-ethylmaleimide-sensitive yam tseem ceeb txuas protein receptors (SNAREs) thiab lwm yam tethering yam muaj feem xyuam rau fusion ntawm daim nyias nyias muab tau los ntawm Golgi, endosomes, orthe plasma membrane nrog omegasome membrane [15] tswj kev loj hlob vesicle.

Cov tiam ntawm PI3P yog qhov tseem ceeb rau lub nucleation ntawm phagophore vesicle, recruitment ntawm PI3P-binding proteins uas koom nrog hauv phagophore expansion, thiab curvatureshaping thiab recruitment ntawm downstream ATG proteins [27]. Kev nrhiav neeg ua haujlwm ntawm PI3P effectors xws li WD-repeat domain phosphoinositide-interacting proteins (WIPIs) rau theomegasome yog qhov tseem ceeb rau autophagosome biogenesis thiab autophagic flux [27,28].

Alfy, alarge scaffolding FYVE domain-muaj protein ntau, yog PI3P effector uas tsom mus rau ubiquitinated aggregates rau autophagosome, yog li koom nrog kev xaiv autophagy [29].

Cov kauj ruam tom ntej no yog kev nrhiav neeg ua haujlwm ntawm microtubule-associated protein 1A/1B-light chain (LC3) tothe phagophore, pab los ntawm ubiquitin-zoo li conjugation systems. Thaum pib, E1 ubiquitinligase ATG7 thiab E2 ubiquitin ligase ATG10 tau koom nrog hauv kev sib txuas ntawm ATG12 rau ATG5 uas txuas ntxiv rau ATG16L1. Cov complex ATG12–ATG5–ATG161L yog qhov tseem ceeb rau muaj kev ua haujlwm ntawm LC3 rau PI3P-positive membranes [27].

Ua ntej, LC3 yog proteolyticallycleaved ntawm C-terminal los ntawm ATG4 protease tsim LC3-I, uas, nyob rau hauv lem, los ntawm kev ua ntawm ATG3 thiab ATG7 thiab ATG12–ATG5–ATG161L, generates LC3-II los ntawm nws Kev khi rau theamine headgroup ntawm phosphatidylethanolamine (PE) hauv phagophore membrane [30,31].

Xws li lipidation ntawm LC3 yog qhov tseem ceeb rau kev nthuav dav thiab kaw ntawm phagophore thiab kev loj hlob ntxiv ntawm autophagosome [32]. Tsis tas li ntawd, lipidated LC3 tau koom nrog kev lees paub ntawm cov khoom thauj tshwj xeeb los ntawm LIR (LC3 thaj chaw sib cuam tshuam) los ntawm cov proteins selectiveadaptor [33]. Lub phagophore nthuav dav thiab elongation tau txhais tsis zoo tab sis kev sib cuam tshuam ntawm WIPI2 nrog ATG9-enriched vesicles yog qhov tseem ceeb rau cov txheej txheem [21].

Ntau qhov haujlwm tau pom tias ntxiv ATG cov proteins tau koom nrog hauv cov kauj ruam kawg ntawm autophagosome biogenesis, tab sis lawv lub luag haujlwm tseem tsis tau txhais meej meej. Kev tshawb fawb pom tias qhov tsis xws luag hauv LC3 ubiquitin-conjugation systems impaired autophagosome kaw [34,35], cuam tshuam cov complexes hauv cov kauj ruam kawg ntawm autophagosome biogenesis.

Qhov kaw ntawm autophagosome vesicles yog kho los ntawm endosomal sorting complex xav tau kev thauj mus los (ESCRT) machinery [36]. Tom qab kaw, autophagosome dissociates los ntawm ER, thiab nws qhov kev loj hlob pib los ntawm kev sib cuam tshuam nrog ntau yam endocytic vesicles.

Autophagosomes tuaj yeem fuse nrog cov endolysosomal compartments, xws li lig endosomes (LE) thiab multivesicular cev (MVB), ib tug feature uas txawv nrog cell hom thiab tej yam physiological mob [37].

Lub fusion ntawm autophagosomes nrog kev ncua MVBsforms ib qho qauv nruab nrab hu ua amphisome uas yuav ntxiv fuse nrog lysosometo degraded [38]. Dephosphorylation ntawm PI3P ntawm autophagosome membrane byphosphoinositide 3-phosphatase ntawm myotubularin protein tsev neeg yuav tsum tau ua ntej lawv fusion nrog lysosomes [39].

Autophagosomes tau muab faib ua ntu zus thoob plaws hauv cytoplasm, thaum lateendosomes thiab lysosomes feem ntau pom muaj nyob hauv thaj tsam perinuclear tab sis kuj muaj cov kab mob neuronal axonal thiab dendritic compartments [40]. Autophagosomes txav raws cov microtubules ntawm lysosomes los ntawm LC3 thiab dynein-dependent mechanisms [41]. Thefusion ntawm autophagosomes nrog lysosomes yog pab los ntawm cov tsev neeg protein sib txawv. RabGTPases nyob hauv thaj chaw ntawm vesicle daim nyias nyias thiab nrhiav cov membrane-tethering proteins uas pab SNAREs hauv cov xwm txheej fusion (saib hauv [42]).

Raws li qhov tshwm sim, qhov depletion ntawm SNAREproteins ua rau tsub zuj zuj ntawm autophagosomes hauv cov hlwb sib txawv [43,44]. Ntawm covRab GTPases uas tswj autophagosome maturation, Rab7 yog recruited mus rau autophagosomemembrane thiab ua raws li ib tug molecular hloov, pab nws binding rau dynein, yog li yooj yim thauj ntawm autophagosome thiab lysosomes mus rau perinuclear cheeb tsam [45]. Rab7-knockdown hlwb qhia kev xaiv tsis zoo ntawm autophagosome fusion nrog lysosome, tab sis tsis nrog LE lossis MVB [45,46].

Tsis tas li ntawd, cov proteins los ntawm GABARAP subfamily (LC3 homologs) tau koom nrog hauv autophagosome maturation, thiab lawv depletion arrestsautophagosome-lysosome fusion [47].

Thaum fusion, acidification ntawm autolysosomallumen los ntawm lub twj tso kua mis proton los yog v-ATPase activates lysosomal hydrolytic enzymes [48], ua rau cargo degradation. Cov txiaj ntsig metabolites muaj rau rov siv dua nyob rau hauv lub cell los yog ua raws li intracellular signaling molecules (Daim duab 2).

Ib qho tseem ceeb ntawm kev tswj hwm macroautophagy yog qhov kev hloov pauv tom qab kev hloov pauv ntawm ntau ATG thiab cov protein uas tsis yog ATG (saib hauv [49]). Qhov no yog qhov tseem ceeb rau kev txwv qhov txuas ntxiv ntawm autophagy thiab tiv thaiv tsis muaj kev tswj hwm kev puas tsuaj ntawm cov ntsiab lus cytoplasmic, uas yuav cuam tshuam rau cov kab mob hauv lub cev thiab tuaj yeem ua rau tuag ntawm tes.

1.2. Kev ua haujlwm ntawm Autophagy hauv Neurons

Neuronal survival cia siab rau ob qho tib si CMA thiab macroautophagy kom sib npaug ntawm cov qib misfolded proteins thiab cov organelles puas ntsoog uas tsis muaj peev xwm yuav diluted los ntawm kev faib cell thiab txhawb nqa cov txheej txheem cellular los ntawm kev rov ua dua metabolites [50].

Kev tshem tawm tsis zoo ntawm cov protein aggregates ua rau muaj kev cuam tshuam ntawm kev thauj mus los ntawm axonal thiab kev hloov pauv loj; Yog li, autophagy yog qhov tseem ceeb rau kev tswj hwm homeostasis thoob plaws hauv lub hlwb neuronal (axon, soma, thiab dendrites).Hauv thaj chaw synaptic, qhov kev hloov pauv ntawm cov protein tsis tu ncua yog qhov tsis tseem ceeb los ua kom tiav cov kev xav tau hauv zos thiab tswj kom muaj kev ua haujlwm ntawm cov protein synthesis thiab degradationcycle [51].

Qhov no yog qhov tseem ceeb tsis tsuas yog txhawb nqa synaptic plasticity [52] tab sis kuj txhawb nqaaxonal homeostasis [53,54]. Tseeb tiag, neuronal stimulation tswj cov qib autophagy, thaum autophagy txhawb nqa synaptic muaj nuj nqi ntawm ob qho tib si ua ntej thiab tom qab synaptic domains [55].

Interestingly, sib nrug los ntawm cov tub ntxhais autophagy machinery, ntau neural-specific regulatoryproteins yuav tsum tau rau autophagy ntawm presynaptic cheeb tsam: Endophillin-A yog ib tug endocyticadaptor uas generates nkhaus daim nyias nyias thiab ua hauj lwm raws li ib tug platform mus nrhiav autophagicproteins, yog li txhawb biomotive genesis, autophagosome. synaptoyanin 1, ib qho lipidphosphatase uas kho cov synaptic vesicle trafficking, kuj yuav tsum tau rau autophagosomebiogenesis [57].

Ntawm qhov tod tes, autophagy tuaj yeem raug tswj tsis zoo ntawm presynapsesthrough Bassoon, scaffold protein uas cuam tshuam nrog ATG5, yog li ua rau nws tsis muaj rau autophagosome biogenesis [58]. Nyob rau hauv cov cheeb tsam tom qab synaptic, autophagy yog qhov tseem ceeb rau kev txhawb nqa synaptic plasticity.

Hauv kev nyuaj siab mus sij hawm ntev (LTD), autophagy yog qhov tseem ceeb rau kev kho kom haum xeeb kev lag luam thiab tshem tawm -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. Interestingly, stimulation ntawm N-methyl-D-aspartate (NMDA) receptorsactivates lub degradation ntawm AMPA receptors los ntawm autophagy [59]. Ntxiv mus, lub hlwb-derivedneurotrophic yam (BDNF) suppresses autophagy nyob rau hauv hippocampal neurons, yooj yim rau lub sij hawm ntev potentiation (LTP) thiab nco persistence nyob rau hauv nas, yog li txhawb lub luag hauj lwm rau autophagy nyob rau hauv synaptic plasticity [60].

Neuronal macroautophagy yog ib qho tseem ceeb mechanism uas tshem tawm cov ntaub ntawv hauv lub cev tsis zoo, thiab ua tau zoo heev hauv cov neurons, nrog rau kev tshem tawm sai ntawm autophagosomes, vim muaj ntau ntawm autophagosomes accumulates hauv neurons tom qab lysosomalinhibition [61].

Hauv cov neurons ntawm CNS thiab tseem ntawm peripheral paj hlwb (PNS), autophagosome biogenesis pib nyob rau hauv neurites thiab synaptic davhlau ya nyob twg cheeb tsam nyob rau hauv lub distalaxon, ces thauj rov qab mus rau lub cell soma los ntawm retrograde txav mus fuse nrog lysosomes active [62].

Autophagosomes dhau los ua kom tiav thaum lawv txav los ntawm distally (neurite tip) mus rau ze ze (cell soma) los ntawm engulfing organelles thiab soluble cargo thiab byincreasing luminal acidification rau npaum cargo degradation. Nyob rau hauv soma, muaj cov neeg sib xyaw ntawm autophagosomes nrog lub xeev sib txawv uas tuaj ntawm distalregions los yog hauv zos tsim [63].

Distal-derived autophagosomes yog khaws cia nyob rau hauv lub somatodendritic compartment thiab tsis tuaj yeem rov qab mus rau axon, whereasthe autophagosomes los ntawm soma tuaj yeem txav mus los ntawm dendrites thiab soma [63].

Hauv cov xwm txheej ib txwm muaj, autophagosomes tsis tshua pom nyob rau hauv cov neurons raws li lawv nrawm nrog lysosomes, qhia tias autophagy muaj txiaj ntsig zoo hauv neurons 'autophagy induction thiab autophagosome clearance hauv [64].

Cov autophagosomes muab tau los ntawm qhov chaw axons muaj cov ntsiab lus cytoplasmic, thiab tsawg kawg 10% ntawm cov pejxeem muaj cov kab mob ntawm mitochondria [62], txhawb lub luag haujlwm rau autophagy-dependent degradation ntawm mitochondria.

Macroautophagy yog qhov tseem ceeb rau neurite shaping thaum nws loj hlob thiab tseem rau neuralplasticity. Kev poob ntawm kev ua haujlwm ntawm ATG16L1, ib qho tseem ceeb autophagic protein, yog txaus rau induces defects hauv nas hlwb tsim [65]. Tsis tas li ntawd, neural-specific deletion ntawm ATG9 ua rau muaj kev txhim kho ntawm axon tracts thiab deficiency neurite outgrowth hauv vitro [66].

Txawm li cas los xij, qhov poob ntawm ATGs thiab cov proteins uas muaj feem cuam tshuam nrog kev laus [67] ua rau muaj kev cuam tshuam ntawm macroautophagy, uas tej zaum yuav ua rau qhov pib lig ntawm ntau cov kab mob neurodegenerative.

Kev sib sau ntawm autophagosomes tshwm sim los ntawm qhov tsis sib xws ntawm lawv qhov tsim thiab degradation [68], uas tau piav qhia hauv Alzheimer's disease (AD), Parkinson's disease (PD), thiab Huntington's disease (HD) [69].

Txawm hais tias kev hloov pauv ntawm autophagy-txog cov noob tsis tau piav qhia raws li qhov cuam tshuam ncaj qha ntawm cov kab mob neurodegenerative, ntau daim ntawv pov thawj txhawb kev cuam tshuam hauv cov txheej txheem macroautophagy thiab nws cov kev tswj hwm muaj feem cuam tshuam nrog neurodegeneration.

Qhov tseeb, kev ua haujlwm tsis zoo ntawm cov txheej txheem autophagic xws li kev puas tsuaj ntawm autophagosome-lysosome fusion [64], tsis zoo lysosomal acidification [70], lossis tsis zoo autophagosometransport [71,72] ua rau tsub zuj zuj ntawm cov tshuaj lom neeg cov protein sib xyaw ua ke thiab ua haujlwm tsis zoo rau cov kab mob hauv lub cev.

Genetic inactivation ntawm ATG5, ATG7, lossis FIP200 hauv CNS ua rau axon o thiab neuron tuag hauv nas, ua rau muaj kev cuam tshuam ntawm lub cev muaj zog [73–75].

Ntxiv mus, ATG5-null nas tuag nyob rau hauv ib hnub ntawm kev yug me nyuam vim neuronal poob los ntawm autophagy impairment [76].Txawm hais tias ntau cov kev tshawb fawb pov thawj qhov tseem ceeb ntawm macroautophagy rau neuronalsurvival thiab muaj nuj nqi, me ntsis paub txog nws cov kev cai hauv neurons thiab glia. .

Kev sib sau ntawm cov proteins tsis zoo lossis kev koom nrog lub cev tau piav qhia zoo hauv ntau cov kab mob neurodegenerative, thiab kev hloov pauv hauv cov haujlwm autophagic tuaj yeem cuam tshuam rau neuronal homeostasis thiab ciaj sia taus. Kev nthuav tawm lub luag haujlwm ntawm autophagy thiab kev tswj hwm hauv neuronal thiab glialfunction yuav yog qhov tseem ceeb rau kev nrhiav cov tswv yim kho tshiab kom tsis txhob muaj kev ua haujlwm tsis zoo ntawm cov neuronal thiab degeneration.

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