Autophagy Defciency nyob rau hauv Neurodevelopmental Disorders Part 2

Txoj kev loj hlob tsis zoo

WIPI2, homolog homolog ntawm cov poov xab Atg18, yog ib qho tseem ceeb regulator ntawm autophagy. WIPI2 cuam tshuam nrog ATG16L1 thiab nrhiav ATG12-ATG5-ATG16L1 complex rau phagophore thiab yog li txhawb nqa LC3 lipidation thiab tom qab autophagosome tsim [25].

Tib neeg lub cim xeeb yog lub tswv yim zoo uas tso cai rau peb khaws cov kev nco txog yav dhau los thiab hu cov ntaub ntawv muaj txiaj ntsig los ntawm lawv txhua lub sijhawm. Txawm li cas los xij, qee tus neeg yuav pom tias lawv muaj kev nco tsis zoo, uas yuav cuam tshuam rau lawv lub neej thiab kev ua haujlwm. Kev tshawb fawb niaj hnub tau lees paub tias cov neeg tswj hwm tseem ceeb tuaj yeem pab tib neeg txhim kho kev nco thiab tiv thaiv lub hlwb.

Cov kws tswj hwm tseem ceeb hais txog cov xwm txheej uas tuaj yeem cuam tshuam rau tib neeg cov metabolism thiab lub neej thiab kev noj qab haus huv. Cov kev tswj hwm tseem ceeb no suav nrog kev noj zaub mov kom zoo, qoj ib ce kom zoo, pw tsaug zog zoo, thiab kev noj qab haus huv ntawm lub hlwb. Cov xwm txheej no ua haujlwm ua ke los pab tib neeg txhim kho lawv txoj kev nco thiab tswj lub hlwb.

Cia peb saib kev noj zaub mov ua ntej. Kev noj zaub mov tseem ceeb heev rau lub hlwb noj qab haus huv vim nws muab cov khoom noj uas peb lub hlwb xav tau. Ntau cov vitamins thiab minerals xws li vitamin B6, folic acid, thiab vitamin E txhua tus ua lub luag haujlwm zoo hauv kev txhim kho lub hlwb thiab kev nco. Tsis tas li ntawd, kev noj zaub mov muaj protein ntau thiab rog tuaj yeem pab peb tiv thaiv thiab txhim kho kev nco.

Kev tawm dag zog kuj yog ib qho tseem ceeb hauv kev ua kom koj lub hlwb noj qab haus huv thiab txhim kho koj lub cim xeeb. Kev tawm dag zog pab txhim kho lub plawv ua haujlwm thiab cov ntshav ncig, thiab txhawb nqa oxygen rau lub hlwb. Tib lub sijhawm, kev tawm dag zog kuj tuaj yeem txhawb lub hlwb kom tso tawm dopamine, endorphins, thiab lwm yam tshuaj hormones, uas tuaj yeem pab txhim kho lub siab, kev xav, thiab kev nco.

Kev pw tsaug zog zoo kuj yog ib qho tseem ceeb tshaj plaws hauv kev saib xyuas lub hlwb. Thaum peb tsaug zog, lub hlwb tshem tawm cov co toxins uas nyob hauv nws, tswj kev sib cuam tshuam ntawm cov neurons, thiab pab peb tiv thaiv thiab txhim kho kev nco. Yog li ntawd, nws yog ib qho tsim nyog yuav tsum tau ua kom tsaug zog txaus thiab pw tsaug zog tsawg kawg yog 7-8 teev hauv ib hnub kom ntseeg tau tias lub hlwb muaj sijhawm txaus los so thiab kho.

Thaum kawg, kev mob hlwb kuj tseem ceeb heev. Ntau yam kev puas siab puas ntsws xws li kev ntxhov siab, kev ntxhov siab, kev ntxhov siab, thiab kev nyuaj siab tuaj yeem cuam tshuam rau lub hlwb thiab kev nco. Yog li ntawd, peb yuav tsum tshem tawm cov kev xav tsis zoo no kom ntau li ntau tau, sib txuas lus nrog cov phooj ywg thiab tsev neeg, koom nrog ntau yam kev ua ub no, thiab ua kom lub siab noj qab nyob zoo.

Hauv cov ntsiab lus, cov tswj hwm tseem ceeb yog cov ntsiab lus tseem ceeb uas pab peb noj qab haus huv thiab txhim kho peb lub cim xeeb. Kev noj zaub mov, kev tawm dag zog, pw tsaug zog zoo, thiab kev noj qab haus huv ntawm lub hlwb ua haujlwm ua ke kom peb lub hlwb noj qab nyob zoo mus ib txhis. Yog li, cia peb pib saib xyuas peb txoj kev noj qab haus huv txij li tam sim no mus! 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 Paub txhawm rau txhim kho lub cim xeeb luv luv

Los ntawm kev ua tiav tag nrho cov exome sequencing rau cov tib neeg cuam tshuam nrog kev loj hlob tsis zoo xws li kev puas hlwb, kev hais lus, thiab kev hais lus tsis zoo, nrog rau lwm yam kev puas siab puas ntsws thiab kev puas siab puas ntsws, kev tshawb fawb tsis ntev los no tau txheeb xyuas qhov kev hloov pauv tshiab uas tsis yog npe hu ua homozygous mutation (V249M) hauv WIPI2 gene [26].

Cov kev tshawb fawb no tau tshaj tawm tias kev hloov pauv ntawm V231M ntawm WIPI2b (suav nrog V249M hauv WIPI2a) txo nws txoj kev cuam tshuam nrog ATG16L1 thiab ATG5-12 nyuaj [26]. Piv nrog rau kev tswj hwm, cov fibroblasts tau los ntawm cov neeg mob nqa V249M kev hloov pauv qhia tau txo qis LC3 lipidation, uas cuam tshuam rau qhov txo qis WIPI2 puncta, thiab tom qab txo qis ntawm autophagy flux [26].

Cov txiaj ntsig tau hais tias qhov kev puas tsuaj ntawm kev tsim autophagosome tuaj yeem ua rau muaj teeb meem neurodevelopmental. Nyob rau hauv txoj kab nrog qhov kev xav no, los ntawm kev ua tag nrho cov exome sequencing ntawm ib tsev neeg uas ib tug ntawm plaub tus me nyuam qhia cortical atrophy loj heev, kev tsis txawj ntse, ataxia, thiab lwm yam paj hlwb, Keays li al. tau txheeb xyuas ib qho kev hloov pauv homozygouscoding (L1224R) hauv VPS15 hauv qhov xwm txheej cuam tshuam[27].

VPS15 yog ib qho tseem ceeb hauv VPS15-VPS34-Beclin1complex uas ua lub luag haujlwm tseem ceeb hauv autophagosomeformation. Cov kev sim ua los ntawm Keays et al.ua qauv qhia tias piv rau kev tswj hwm, cov dermal fibroblasts tau los ntawm cov tib neeg cuam tshuam qhia cov qib protein tsawg ntawm VPS15, VPS34, thiab Beclin1, txo qis LysoTracker staining, thiab nce qib protein ntawm p62, ib qho autophagy cargo receptor [27]

Kev tshawb fawb ntxiv qhia tau hais tias ectopic qhia ntawm cov tsiaj qus-hom VPS15 hauv L1224R cov neeg mob hlwb nce cov protein ntau ntawm VPS15, stabilizes VPS34 thiab Beclin1, thiab txo cov qib protein ntawm p62 [27].

Cov kev tshawb pom no qhia tau hais tias L1224R mutationin VPS15 yog txuam nrog tib neeg neurodevelopmentaldisorders los ntawm kev cuam tshuam kev ua haujlwm ntawm VPS15-VPS34-Beclin1 complex hauv autophagy.ATG7 yog ib qho tseem ceeb effector enzyme rau canonicalautophagy.

Tsis ntev los no, los ntawm kev ua cov tshuaj ntsuam genetic andclinical, Taylor et al. tau txheeb xyuas qhov kev hloov pauv tsis zoo thiab poob ntawm kev ua haujlwm hauv ob qho tib si ATG7 alleles hauv 12 tus neeg los ntawm tsib tsev neeg tsis sib xws, uas ua rau muaj kev cuam tshuam ntawm cov txheej txheem neurodevelopmental xws li ataxia thiab kev loj hlob qeeb [15].

Cov kev sim ua hauv thefibroblasts thiab cov pob txha pob txha tau muab los ntawm cov neeg mob qhia tias qhov kev qhia ntawm ATG7 tau ploj zuj zus mus rau hauv cov neeg mob tau txais cov hlwb, ua rau muaj qhov tsis zoo LC3lipidation thiab autophagy flux [15].

Cov kev sim ua kom muaj txiaj ntsig zoo hauv cov nas thiab cov poov xab tau lees paub qhov kev ua haujlwm tsis zoo uas tshwm sim los ntawm kev hloov pauv tsis zoo hauv ATG7 [15]. Ua ke, txoj kev tshawb no nthuav tawm lub luag haujlwm tseem ceeb ntawm basal autophagy hauv tib neeg neural txoj kev loj hlob thiab kev ncaj ncees.

Autophagy dysregulation hauv neurodevelopmentaldisorders

Cov pov thawj loj hlob qhia txog qhov tsis zoo ntawm mTORin ASD [28–30]. mTOR yog lub hauv paus tswj hwm ntawm cov txheej txheem sib txawv nrog rau autophagy. mTOR yog tswj tsis zoo los ntawm tuberous sclerosis complex 1/2 (TSC1/2) [16, 31, 32].

Cov kev tshawb fawb yav dhau los tau tshaj tawm tias TSC2 ± nas tso tawm qhov ua rau muaj kev cuam tshuam ntawm mTOR, thaiv ntawm autophagy, thiab qhov tshwm sim ntawm tus txha nqaj qaum [33]. Tsis tas li ntawd, ib qho mTOR inhibitor rapamycincan kho tus txha caj qaum pruning tsis xws luag thiab ASD-txog tus cwj pwm hauv TSC2 ± nas, tab sis tsis nyob hauv TSC2 ±: ATG7 cKOmice [33].

Ib txoj kev tshawb fawb tsis ntev los no tau tshaj tawm cov txiaj ntsig zoo sib xws hauv parvalbumin (PV) cell-restricted TSC1 conditional haploins txaus thiab knockout nas, uas qhia tau hais tias tsis muaj zog autophagy dysfunctions, poob ntawm perisomaticinnervation, thiab kev coj cwj pwm tsis zoo [34].

Ntxiv mus, kev kho mob nrog rapamycin nyob rau lub sijhawm rhiab heev cawm PV cell txuas thiab kev coj tus cwj pwm hauv TSC1conditional haploins txaus nas [34]. Sib nrug los ntawm TSC1/2 cov qauv ntawm ASD, cov kev tshawb fawb tsis ntev los no tau tshaj tawm cov kev qhia tsis zoo ntawm autophagy-related proteinBeclin1 hauv cov qauv tsiaj ntawm ASD suav nrog Cc2d1a± thiab ADNP ± nas [35, 36].

Cov kev tshawb fawb no qhia tias dysregulation ntawm autophagy yuav pab tau rau neuronalpathology thiab aberrant social cwj pwm nyob rau hauv ASD.Fragile X syndrome (FXS), ib tug ua genetic cause of autism, yog ib tug heritable daim ntawv ntawm kev txawj ntse tsis taus xws li autistic cwj pwm, tsis txaus siab mloog, kev xav lability, impaired kev txawj ntse, thiab lwm yam kev tsis taus ntawm lub paj hlwb [37–39].

Fragile X hlwb retardation (Fmr1) yog ib tug ua rau cov noob rau FXS [40]. Fragile Xmental retardation protein (FMRP), encoded los ntawm Fmr1 noob, yog ib qho RNA-binding protein uas nruj tswj kev ua haujlwm ntawm ntau cov neuronal mRNAs tseem ceeb toneuronal txoj kev loj hlob thiab synaptic plasticity [41, 42].Fmr1-KO nas yog ib tug tus qauv zoo ntawm FXS[40].

Cov kev tshawb fawb yav dhau los tau tshaj tawm qhov tsis zoo ntawm mTOR teeb liab hauv FXS nas thiab tib neeg nrog FXS [43, 44]. Ib txoj kev tshawb fawb tsis ntev los no qhia tau hais tias cov cim biochemical ntawm autophagy xws li LC3IIpuncta, daim ntawv nquag ntawm p-ULK1 thiab p-Beclin1, thiab qhov tshwm sim autophagy flux tau txo qis, thaum p62 tau khaws cia, hauv hippocampal neuronsof Fmr1-KO nas, tej zaum yog vim deregulatedmTOR signaling [45].

Kev tshawb nrhiav tshuab qhia tau hais tias mTORC1 kev ua haujlwm tau txhim kho thiab Raptor, lub ntsiab lus txhais ntawm mTORC1, translocatesto lub lysosome [45]. Thiab tshwj xeeb knockdown ntawm Raptorin lub hippocampal neurons activates autophagy andrescues lub impaired synaptic plasticity thiab cognitionin Fmr1-KO nas [45].

Cov kev tshawb pom qhia tias lawvTOR-dependent autophagy yog qhov tsis zoo nyob rau hauv FXS thiab ua kom autophagy los ntawm mTOR inhibition tiv thaiv cov neuronal deficits hauv FXS.

Cov kev tshawb fawb tsis ntev los no tau tshaj tawm txog dysregulation ofmTOR-dependent autophagy nyob rau hauv lwm yam neurodevelopmental mob xws li Schaaf-Yang syndrome (SHFYNG) thiab Koolen-de Vries syndrome (KdVS) [46, 47].

SHFYNG yog ib qho kab mob neurodevelopmental uas tshwm sim los ntawm MAGEL2 kev hloov pauv thiab cov neeg mob nrog SHFYNG qhia txog kev noj zaub mov nyuaj, kev tsis taus ntawm kev txawj ntse, thiab nce ntau ntawm ASD [48-50]. Schaaf et al. tau tshaj tawm tias lawvTOR kev ua haujlwm tau nce ntxiv, nrog rau kev txo qis hauv cov neeg mob autophagy hauv MAGEL2 null nas thiab fibroblasts tau los ntawm cov neeg mob SHFYNG [46].

Lub inducedpluripotent qia cell (iPSC)-derived neurons los ntawm SHFYNG cov neeg mob qhia impaired dendrite tsim uas yuav cawm tau los ntawm kev kho mob nrog rapamycin [46]. KdVS yog ib qho kab mob neurodevelopmental uas tshwm sim los ntawm kev hloov pauv nrog kev ua haujlwm tsis zoo hauv KANSL1 noob thiab cov neeg mob nrog KdVS tshwm sim qaug dab peg, congenital malformations, thiab kev loj hlob qeeb [51-53].

Feem ntau tsis ntev los no, Kasri et al. Tau tshaj tawm tias IPSC-derivingons

Mechanistically, lawv pom tias nyob rau hauv cov iPSC-derived neurons, mTOR kev ua tau zoo thiab cov lysosome muaj nuj nqi txo, yog li tiv thaiv cov clearance ntawm autophagosome [47] .Tau ua ke, cov kev tshawb pom no qhia tias mTOR-dependent autophagy yog cuam tshuam nyob rau hauv cov neurodevelopmental teeb meem.

Autophagy tswj neurogenesis

Cov pov thawj uas poob-ntawm-function hloov pauv hauv cov noob tseem ceeb autophagy ua rau cov kab mob neurodevelopmental ua rau pom lub luag haujlwm tseem ceeb ntawm autophagy hauv neurodevelopment. Dab tsi yog lub hauv paus ntawm kev ua haujlwm ntawm autophagy hauv kev tswj hwm kev tsim kho neuro?

Los ntawm kev zom cov tshuaj lom cov proteins oraggregates thiab cov kab mob puas, autophagy criticallyregulates neuronal plasticity thaum lub sij hawm kev loj hlob ntawm neuronal. Muab qhov kev txaus siab loj hlob hauv lub luag haujlwm ntawm autophagyin neural proliferation thiab kev saib xyuas ntawm cov hlwb neuronalstem (NSC), ntawm no peb tshuaj xyuas cov pov thawj txuas rau autophagy rau neurogenesis.

Los ntawm kev siv cov tswv yim knockout, cov kev tshawb fawb yav dhau los tau tshawb xyuas lub luag haujlwm ntawm autophagy hauv embryonic neurogenesis [55]. Jiao et al. tau qhia txog lub luag haujlwm tseem ceeb ntawm autophagy hauv cortical neurogenesis thaum lub sij hawm ntxov hlwb [56].

Lawv pom tias ATG5 qhia tau nce ntxiv thaum lub sij hawm cortical txoj kev loj hlob thiab kev sib txawv [56]. Kev Tiv Thaiv ntawm ATG5 los ntawm kev siv electroporation ntawm luv luv hairpin shRNAs ua rau txo qis neural progenitor cells (NPCs) sib txawv, thiab ua rau muaj kev cuam tshuam ntawm kev tsis zoo ntawm cortical neurons [56].

Kev tshawb nrhiav tshuab qhia tau hais tias ATG5-kev kho mob autophagy tswj txoj hauv kev -Catenin signaling, uas yog qhov tseem ceeb rau NPCs kev loj hlob thiab kev sib txawv hauv kev tsim kho neurodevelopment.

Lawv tau pom tias autophagy koom tes nrog -Catenin los hloov kho qhov kev loj hlob thiab kev sib txawv ntawm cortical NPCs hauv embryonic neurogenesis thaum lub sij hawm kev loj hlob ntawm hlwb [56]. Tsis tas li ntawd, lwm txoj kev tshawb fawb tau tshaj tawm tias kev txo qis ntawm ATG5 cuam tshuam kev sib txawv ntawm astrocyte hauv vitro thiab hauv cov nas cortex, thaum overexpression ntawm ATG5 txhim kho astrocytedifferentiation [57].

Cov ntaub ntawv pov thawj ntxiv tau qhia tias dhau los ntawm kev txhawb nqa kev degradation ntawm SOCS2, ATG5-mediated autophagy activates JAK2-STAT3 signaling, uas tswj kev sib txawv ntawm astrocytes, thaum qhov kev sib txawv ntawm cov astrocyte tsis zoo tshwm sim los ntawm ATG5deficiency tuaj yeem cawm tau los ntawm [SOCS2down. 57].Cov kev tshawb fawb no qhia tau hais tias ATG5-mediated autophagyregulates ob leeg neurogenesis thiab gliogenesis thaum ntxov kev loj hlob.

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