Autophagy Defciency nyob rau hauv Neurodevelopmental Disorders Part 3

FIP200 (tseem hu ua Rb1cc1) yog ib qho tseem ceeb gene forautophagy induction. Guan cov pab pawg yav dhau los tau tshaj tawm tias kev txo qis ntawm FIP200 ua rau muaj kev poob qis ntawm NSCs thiab cuam tshuam kev sib txawv neuronal hauv cov nas tom qab yug me nyuam, uas tuaj yeem cawm tau los ntawm kev kho mob nrog cov tshuaj tua kab mob antioxidant N-acetylcysteine ​​[58].

Nrog kev txuas ntxiv mus tob zuj zus ntawm kev tshawb nrhiav caj ces nyob rau xyoo tas los no, tib neeg muaj kev nkag siab tob txog kev sib raug zoo ntawm cov noob thiab kev nco. Peb txhua tus muaj qee qhov kev cuam tshuam ntawm caj ces ntawm peb lub cim xeeb.

Qee tus neeg yug los nrog kev nco zoo heev, thaum lwm tus tuaj yeem hnov ​​​​qab yooj yim dua lossis nyuaj rau nco qab. Qhov tseem ceeb tshaj plaws nyob rau hauv ntau yam noob hauv peb lub cev thiab lawv qhia li cas. Qee cov noob no suav tias yog "cov noob tseem ceeb" thiab ua lub luag haujlwm tseem ceeb hauv peb lub peev xwm nco thiab kev txawj ntse.

Tshwj xeeb, cov kws tshawb fawb pom tau tias cov noob tseem ceeb yog qhov tseem ceeb uas tuaj yeem cuam tshuam kev loj hlob thiab kev ua haujlwm ntawm peb lub hlwb. Cov noob no tuaj yeem cuam tshuam rau peb lub cell ua haujlwm sib txawv, cuam tshuam rau peb txoj kev paub thiab kev coj cwj pwm.

Tsis tas li ntawd, cov noob tseem ceeb tau xav tias yuav hloov pauv peb cov synapses thiab ua rau lub hlwb metabolic nce ntxiv, nce cov neurons, thiab txhim kho kev nco thiab kev kawm. Yog li, kev tshawb nrhiav caj ces tuaj yeem pab peb nkag siab zoo txog kev nco thiab kev paub txog kev loj hlob thiab yuav ua li cas nrog kev kawm thiab kev nco tsis zoo.

Nws yog tsim nyog hais tias cov noob tseem ceeb nyob hauv cov haujlwm tshwj xeeb hauv tib neeg genome. Cov chaw no tau xav tias yog thaj chaw cuam tshuam nrog kev paub thiab kev loj hlob ntawm lub paj hlwb, qhia txog qhov tseem ceeb ntawm cov noob no rau tib neeg kev txawj ntse thiab kev nco.

Yog li ntawd, peb tuaj yeem hais tias cov noob tseem ceeb yog qhov tseem ceeb ntawm tib neeg kev nco qab thiab lawv ua lub luag haujlwm tseem ceeb hauv peb txoj kev paub thiab kev txawj ntse. Los ntawm kev nkag siab zoo dua cov noob no, peb tuaj yeem nkag siab ntau dua rau qhov xwm txheej ntawm lub peev xwm nco, pab peb kawm txog kev txhim kho kev nco thiab kev txawj ntse. Nws tuaj yeem pom tias peb yuav tsum txhim kho kev nco, thiab Cistanche deserticola tuaj yeem txhim kho kev nco, vim Cistanche deserticola muaj antioxidant, tiv thaiv kev mob, thiab tiv thaiv kev laus, uas tuaj yeem pab txo qis oxidation thiab inflammatory tshwm sim hauv lub hlwb, yog li tiv thaiv cov kev noj qab haus huv ntawm lub paj hlwb. Tsis tas li ntawd, Cistanche deserticola kuj 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 kev loj hlob ntawm kev paub tsis meej thiab cov kab mob neurodegenerative.

Nyem tam sim no txhawm rau txhim kho koj lub cim xeeb ua haujlwm

Tsis ntev los no, tib pab pawg tau pom cov pov thawj tias microglial dysregulation ua rau muaj kev cuam tshuam ntawm neurogenesis hauv FIP200-null NSCs los ntawm FIP200; p53hGFAP 2cKO nas [59].

Mechanistically, txoj kev tshawb no qhia tau hais tias ablation ntawm FIP200 ua rau muaj zog infiltration ntawm microgliainto lub subventricular cheeb tsam thiab tom qab microglia ua kom nyob rau hauv FIP200; p53hGFAP 2cKO nas [59].

Inhibition ntawm microglia infiltration thiab ua kom muaj peev xwm cawm tau cov neurogenesis tsis zoo hauv cov nas 2cKO[59]. Cov kev tshawb pom no qhia tau hais tias FIP200-mediatedautophagy plays lub luag haujlwm tseem ceeb hauv kev tswj cov neurogenesis hauv postnatal NSCs los ntawm kev tswj ntawm microgliamigration thiab ua kom muaj zog. Ntxiv nrog rau embryonic neurogenesis, cov neeg laus neurogenesis tuaj yeem tswj hwm los ntawm autophagy [60].

Lub Notch signaling txoj hauv kev muaj lub luag haujlwm tseem ceeb hauv cov neeg laus neurogenesis [61]. Cov kev tshawb fawb yav dhau los tau pom tias kev ua kom tsis muaj teeb meem cuam tshuam qhov kev loj hlob thiab kev sib txawv ntawm NSCs hauv cov neeg laus lub hlwb [62, 63].

Rubinsztein pawg tau tshaj tawm tsis ntev los no hais tias Notch1, plasma membrane-nyob receptor nyob rau hauv Notch signaling, yog degraded los ntawm autophagy los ntawm ATG16L1, acrucial autophagy protein [64] Lawv pom tau hais tias ATG16L1 protein theem tau txo, whereas cov theem ntawm Notch signaling proteins NI Notch thiab Hes1 tau nce ntau hauv lub hlwb ntawm ATG16L1-hypomorph nas [64]. Lawvntxiv tau pom qhov tsis txaus ntseeg ntawm NSCs thiab cov cortiplateslate me me hauv ATG16L1-hypomorph piv nrog cov nas tswj[64]. Siv BrdU daim ntawv lo, lawv tau pom tias tus naj npawb ntawm BrdU-zoo hlwb txo qis hauvATG16L1-hypomorph nas piv nrog cov kev tswj ntawm 9-11 lub hlis [64]. CovCov txiaj ntsig tau qhia tias ATG16L1-kev kho mob autophagy tswj ob qho tib si embryonic thiab cov neeg laus neurogenesis los ntawm kev tswj cov protein degradation nyob rau hauv txoj kev taw qhia.

Lub Forkhead Box O (FOXO) cov proteins yog ib chav kawm ntawm kev txuag kev hloov pauv uas tswj cov kev pabcuam geneexpression koom nrog ntau lub xovtooj ntawm tes [65]. Cov kev tshawb fawb yav dhau los tau tshaj tawm lub luag haujlwm ntawm FOXO proteins hauv kev tswj hwm ntawm cov neeg lausNSCs homeostasis thiab autophagy induction [66-68].

Ib txoj kev tshawb fawb tsis ntev los no tau pom tias FOXO3 ncaj qha tswj txoj hauv kev autophagy los tswj cov proteostasis hauv cov neeg laus NSCs [69]. Wurst et al. Tsis ntev los no tau tshaj tawm tias qhov xwm txheej knockout ntawm FOXO1/3/4 hauv cov neeg lausNSCs los ntawm kev siv GLAST::CreERT2 impairs autophagyflux ob qho tib si hauv vitro thiab hauv vivo [70]. FOXO1 / 3deficiency ua rau hloov pauv dendrite thiab txha nraub qaum ntawm cov neeg laus tsim cov neurons thiab ua rau tsis muaj sia nyob ntev thaum kawg [70].

Cov pov thawj ntxiv qhia tau hais tias autophagy inducer rapamycin tsis yog tsuas yog cawm tau qhov tsis zoo autophagy flux hauv NSCs tab sis kuj thim rov qab cov phenotypes ntawm dendrite thiab qaum ntawm cov neeg laus tsim cov neurons nrog FOXO1/3/4 deficiency [70]. Cov kev tshawb pom qhia tias FOXO proteins tswj cov neuronal morphogenesis los ntawm kev saib xyuas ntawm autophagy flux thaum cov neeg laus neurogenesis.

Autophagy tswj presynaptic thiab postsynapticdevelopment thiab synaptic kev ua ub no
Neurons yog cov hlwb postmitotic uas tau khaws cia rau lub neej ntawm lub cev. Txawm li cas los xij, cov synapses ntawm neurons yog qhov muaj zog heev, tshwj xeeb tshaj yog thaum ntxov lub neej vim tias qhov kev loj hlob ntawm synapses tau ntsib thawj zaug nce thiab txo qis ua ntej kev txhim kho synapse.

Thaum lub sij hawm synapsedevelopment, cov khoom ntawm synapses tuaj yeem hloov pauv thiab hloov pauv, thaum cov kab mob neural tshiab tau tsim nyob rau hauv cov xwm txheej xws li kev kawm thiab kev ntxhov siab.

Muaj pov thawj pom tau tias autophagy plays lub luag haujlwm hauv kev tsim synapse thiab pruning, ib txheej txheem pab txhawb kom muaj kev sib txuas ntawm cov neuronal exuberant [71]. Tsis tas li ntawd, autophagy kuj tseem tuaj yeem tswj cov kev ua haujlwm ntawm synaptic, uas yog nyob ntawm synapse transmission thiab plasticity.

Autophagy tswj presynaptic thiab postsynapticdevelopment

Thaum ntxov txoj kev loj hlob, autophagy yog yuav tsum tau rau pathfinding thiab synaptic vesicle pawg tsim thaum ntxov synaptogenesis [72–74]. Cov kev tshawb fawb yav dhau los tau pom tias poob ntawm autophagic scaffolding proteinALFY ua rau tsis ua haujlwm hauv axon kev taw qhia thiab outgrowthin txoj kev loj hlob ntawm nas hlwb [75].

Neural-specificdepletion ntawm ATG9 ua rau muaj qhov txawv txav ntawm kev loj hlob ntawm axon tracts nyob rau hauv nas hlwb thaj tsam nrog rau lub corpuscallosum thiab anterior commissure [73]. Hauv C. elegansinterneuron, autophagy tswj presynaptic assemblyand axon outgrowth dynamics, uas yog spatial tswj los ntawm kev sib koom tes ntawm ATG9 thiab synapticvesicle kinesin, KIF1A/UNC-104 [76].

Raws li qhov kev xav no, ib qho kev tshawb fawb yav dhau los ua hauv Drosophilaindicated tias Atg1 (ib qho ortholog ntawm ULK1 hauv S. cerevisiae) mutant ua rau txo tag nrho cov neuromuscular hlws ris (NMJ) cheeb tsam thiab txo cov synapses [77].

Txawm li cas los xij, overexpression ntawm wildtype Atg1 nce NMJsynaptic bouton tooj nyob rau hauv ib qho autophagy-dependentmanner [77].Nyob rau hauv postsynaptic site, autophagy tau pom tias koom nrog hauv synaptic pruniDeficienciescies hauv autophagyresult nyob rau hauv ib qho overabundance ntawm dendriticutism zoo li 3 qhov kawg, ]. Piv txwv li, thawj hippocampal neuron kab lis kev cai nrog txo Atg7 qhia pom tau nce PSD95density, ib qho cim rau postsynaptic abundance [33] Cov txiaj ntsig zoo sib xws tau pom hauv cov qauv nas nrog Atg7knockdown [33].

Lwm txoj kev tshawb fawb tau pom tias NMJs los ntawm autophagy-deficient neurons nthuav tawm postsynaptic foldswithout presynaptic axon terminals as opposed to lawv, qhia txog qhov txawv txav postsynaptic pruning [78]. Cov txiaj ntsig no qhia tau tias basal autophagy tuaj yeem ua lub luag haujlwm tseem ceeb hauv qee qhov postsynaptic receptor degradation thiab postnatal spine pruning.

Autophagy tswj cov haujlwm synaptic

Ntau kab ntawm cov pov thawj qhia tau hais tias autophagy modulates neurotransmitter tso tawm thiab neural plasticity.Marijn Kuijpers li al. Tsis ntev los no pom tias cov neurotransmission thiab calcium rhiab heev nce hauv thawj hippocampus excitatory neurons nyob rau hauv Atg5knock-miceouse vim deregulation ntawm ER turnover [79].

Ntxiv mus, ib txoj kev tshawb fawb yav dhau los pom tias depletion of autophagy los ntawm kev siv dopaminergic neuron-tshwj xeeb Atg7knock-out nas mosignificantlyntly cuam tshuam rau dopaminerelease thiab reuptake [80] Txoj kev tshawb no ntxiv qhia tias striatal slices los ntawm Atg7 DAT:: Cree nas tau nce dopamine tso tawm thiab kev sim cyclic. txhim kho presynaptic rov qab tom qab ua khub-pulse stimulation.

Ntxiv mus, kev kho mob rapamycin txo qis kev txhawb nqa-evoked dopamine tso tawm inslices los ntawm Atg7 DAT::Cre nas [80] Cov kev tshawb fawb no muab pov thawj rau lub luag haujlwm ntawm presynaptic autophagy hauv kev tswj hwm ntawm neurotransmission.

Ib txoj kev tshawb fawb tsis ntev los no tau qhia tias autophagy tswj kev txhim kho-txog synaptic plasticity thiab nco [81]. NMDA receptor-dependent long-term kev nyuaj siab (NMDAR-LTD) yog ib daim ntawv ntev-ntev ntawm synaptic plasticity [82]. Qhov induction ntawm NMDAR-LTD yog kho los ntawm kev tshem tawm ntawm AMPA receptors los ntawm postsynapticmembranes mus rau lig endosomes rau degradation [83]. Nws yog induced nyob rau hauv thaum ntxov theem ntawm neuronal txoj kev loj hlob thaum lub sij hawm loj txo nyob rau hauv neeg laus thaum lub sij hawm CNS txoj kev loj hlob.

Kev tswj hwm ntawm NMDAR-LTD hauv cov neeg laus yog qhov tseem ceeb rau kev tsim lub cim xeeb. Shen etal. qhia tias autophagic flux hauv CA1 neurons tau hloov pauv hloov pauv thaum lub sijhawm induction ntawm NMDAR-LTD. Autophagy inhibition ua rau txo qis ntawm endocytic recycling thiab yuav tsum tau rau AMPA receptor internalization thiab synaptic kev nyuaj siab hauv mouseCA1 neurons.

Hauv cov neeg laus, autophagy yog tswj hwm kom txo qis qhov tsis txaus ntseeg ntawm LTD, yog li tiv thaiv qhov cuam tshuam ntawm LTD ntau dhau ntawm kev nco ua ke [81]. Tsis tas li ntawd, Compans et al. pom tias autophagyis xav tau rau kev degradation ntawm T19-phosphorylatedform ntawm PSD95 nyob rau hauv NMDAR-LTD induction, uas ua rau ib tug depletion ntawm PSD95 los ntawm synapses thiab nws thiaj li ua rau lub sij hawm luv luv plasticity los txhim kho neuronalresponsiveness ntawm kev nyuaj siab synapses [84].

Ib txoj kev tshawb fawb tsis ntev los no tau pom tias kev sib koom ua ke ntawm mTOR-dependent autophagy cawm kev tiv thaiv ntawm NMDAR-LTD induced los ntawm kev cuam tshuam kev sib koom ua ke ntawm CREB thiab CRTC1, ob qho tseem ceeb ntawm kev hloov pauv rau lub sij hawm ntev synaptic potentiation [85]. kev ua haujlwm ntawm autophagy hauv kev tswj hwm ntawm synaptic plasticity thiab nco (Daim duab 1).

Cov lus xaus

Cov pov thawj loj hlob tau hais txog lub luag haujlwm tseem ceeb ntawm autophagy hauv kev tswj hwm kev tsim kho neurodevelopment thiab synapticplasticity.

Kev hloov pauv ntawm autophagy tuaj yeem ua rau qhov txawv txav neurodevelopment thiab malfunction ntawm synapsesin lub hlwb. Tsis ntev los no tib neeg caj ces thiab cov kev tshawb fawb soj ntsuam tau txheeb xyuas qhov sib txuas ntawm kev hloov pauv hauv lub cev hauv cov noob caj ces cuam tshuam rau cov kab mob neurodevelopmental (Table 1).

Txawm li cas los xij, qhov laj thawj ntawm autophagydeficiency nyob rau hauv tus kab mob tseem tos kom pom ntxiv rau cov haujlwm uas tsis yog autophagy cuam tshuam nrog ntau cov noob caj noob ces. Nws tseem yog qhov nyuaj heev los hais txog lub luag haujlwm tshwj xeeb ntawm autophagy vim qhov nyuaj ntawm kev saib xyuas autophagy muaj nuj nqi ncaj qha hauv tib neeg lub hlwb. Thaum cov qauv nas yog cov cuab yeej tseem ceeb rau kev txiav lub ru tsev rau autophagy hauv neurodevelopment thiab diferentiation (piv txwv li, engineering autophagy noob deletion inCNS), qhov ua tau zoo ntawm cov noob autophagyhomologous betwrodentsdent humansuman werenoticed, thiab tej zaum yuav nyuaj rau kev txhais lus [2].

Ib txoj kev tshawb fawb tsis ntev los no tau txheeb xyuas qhov kev hloov pauv tsis zoo thiab poob ntawm kev ua haujlwm nyob rau hauv ob qho tib si ATG7 alleles hauv cov neeg mob uas muaj cov kab mob neurodevelopmental nyob rau hauv tsib tsev neeg tsis sib xws [15]. Txawm hais tias tsis ua tiav ntawm ATG7protein, cov neeg mob nqa cov kev hloov pauv tsis zoo ntawm ATG7 tau ncav cuag cov neeg nyob hauv lub neej [15,87]. Hauv qhov sib piv, nas tsis muaj Atg7 noob tuag ntxov tom qab yug menyuam.

Cov ntaub ntawv qhia tias tib neeg muaj kev tiv thaiv ntau dua ntawm kev poob ntawm ATG7 lossis ATG7-kev kho mob autophagy.Lwm piav qhia yog tias cov haujlwm ntawm tes uas tuaj yeem them rov qab rau qhov poob ntawm ATG7 muaj nuj nqi hauv kev ciaj sia muaj zog dua rau tib neeg dua li cov nas. Txhawm rau txiav tawm ncaj qhaATG7-kev kho mob autophagy hauv cov neeg mob neurodevelopment inhumans, kev sim yav tom ntej yuav tsum siv tib neeg cov neurons nqa cov mutants sib xws. Covtib neeg cov neurons tau txais los ntawm induced pluripotent qia hlwb (iPSCs) yuav muab ib qho qauv tseem ceeb los tshawb xyuas cov txheej txheem uas yog qhov tsis muaj autophagy ua rau cov kab mob neurodevelopmental, thiab kuaj cov tswv yim kho mob los ntawm kev rov ua haujlwm autophagy.

Kev lees paub

Peb ua tsaug rau cov tswv cuab ntawm Yue lab thiab Lu lab rau lawv cov lus qhia.

Cov neeg sau ntawv pab txhawb

ZY, JL, thiab ZD tsim qhov project. ZD thiab XZ tshawb nrhiav cov ntaub ntawv thiab sau cov ntawv sau. ZY, JL, ZD, thiab XZ kho thiab kho cov ntawv sau.Tag nrho cov neeg sau ntawv nyeem thiab pom zoo cov ntawv sau nyiaj txiag.

Nyiaj txiag

Txoj kev tshawb no tau txais kev txhawb nqa los ntawm ChinaMinisterr of Science thiab Technology grantMoST-2017YFE0120100, Science thiab Technology Development Fund, Macau SAR (No. 0110/2018/A3, 0128/2019/A3, China), University of Macaugrants ( No. MYRG2019-00129-ICMS, Tuam Tshoj) muab khoom plig rau Jia-Hong Lu, thiab NIH/R01NS060123 thiab R01 R01AG072520 muab rau Zhenyu Yue.

Muaj cov ntaub ntawv thiab cov ntaub ntawv

Tsis siv tau.

Kev pom zoo ntawm kev ncaj ncees thiab kev tso cai los koom

Tsis siv tau.

Tso cai rau kev tshaj tawm

Tsis siv tau.

Kev nyiam sib tw

Cov kws sau ntawv tshaj tawm tias lawv tsis muaj kev sib tw nyiam.

AutoDetailsls

State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao SAR 999078, Suav. 2 Department of Neurology, Friedman Brain Institute, Icahn Tsev Kawm Ntawv ntawm Tshuaj ntawm Mount Sinai, New York, NY 10029, USA. 3 Department of Geriatrics, Xiangya Tsev Kho Mob, Central South University, Changsha 410008, Hunan, Suav.

Cov ntaub ntawv

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