Crosstalk Ntawm Ntau DNA Kho Txoj Kev Pab Rau Cov Kab Mob Neurodegenerative Part 3

5.1. DDR thiab Autophagy

Tsis muaj txiaj ntsig kev tshem tawm uas qhia tias muaj kev puas tsuaj autophagy yog ib qho ntawm cov yam ntxwv ntawm NDDs. Thaum lub sij hawm AD pathogenesis, ob qho tib si impaired autophagosome synthesis thiab txo kev tshem tawm ntawm autophagic substrates tau pom [152-154].

Autophagy yog txheej txheem ntawm tus kheej decomposition thiab rov ua dua ntawm cov hlwb, uas tuaj yeem pab peb tshem tawm cov laus, puas, thiab tsis muaj txiaj ntsig organelles thiab cov proteins. Txawm li cas los xij, nrog lub hnub nyoog nce thiab kev ua neej tsis zoo, tib neeg lub cev ua haujlwm autophagy maj mam poob qis, uas tuaj yeem ua rau peb txoj kev noj qab haus huv thiab kev nco.

Cov kev tshawb fawb tau pom tias muaj kev sib raug zoo ntawm autophagy thiab nco. Kev poob qis ntawm autophagy muaj nuj nqi yuav ua rau cov khoom khib nyiab hauv lub hlwb, yog li cuam tshuam rau cov metabolism hauv ib txwm thiab cov teeb liab xa mus rau hauv cov hlwb, ua rau kev nco tsis zoo thiab kev txawj ntse. Cov txheej txheem autophagy ib txwm tuaj yeem txhawb kev tsim thiab rov ua dua tshiab ntawm cov hlwb hlwb, tswj kev noj qab haus huv ntawm hlwb hlwb, thiab yog li pab txhim kho kev nco thiab kev txawj ntse.

Yog li ntawd, peb yuav tsum nquag tswj hwm kev ua haujlwm autophagy thiab txhim kho peb qib autophagy los ntawm kev ua neej nyob zoo thiab kev hloov pauv kev noj haus. Piv txwv li, peb yuav tsum tsis txhob noj ntau dhau ntawm cov khoom noj tsis zoo xws li qab zib thiab rog, thiab noj ntau cov txiv hmab txiv ntoo thiab zaub, cov nplej, thiab lwm yam khoom noj uas muaj cov antioxidants thiab cellulose, uas tuaj yeem pab txo qis kev tsim cov dawb radicals thiab txhawb kev loj hlob ntawm cov kab mob. txheej txheem autophagy. Tsis tas li ntawd, peb yuav tsum ua kom muaj kev tawm dag zog me ntsis, ua kom lub siab zoo siab, zam kev ntxhov siab thiab ntxhov siab, thiab lwm yam, uas yuav pab txhim kho autophagy thiab tswj lub hlwb noj qab haus huv thiab nco zoo.

Feem ntau, muaj tseeb muaj kev sib raug zoo ntawm autophagy thiab nco, tab sis peb tuaj yeem tswj hwm peb qib autophagy los ntawm kev ua neej zoo thiab kev noj haus, tiv thaiv peb lub hlwb thiab nco, thiab txav mus rau lub neej noj qab haus huv thiab zoo dua. Nws tuaj yeem pom tau tias peb yuav tsum txhim kho peb lub cim xeeb, thiab Cistanche tuaj yeem txhim kho kev nco zoo vim Cistanche tseem tuaj yeem tswj hwm qhov sib npaug ntawm cov neurotransmitters, xws li nce qib ntawm acetylcholine thiab kev loj hlob, uas tseem ceeb heev rau kev nco thiab kev kawm. Tsis tas li ntawd, Cistanche tseem tuaj yeem txhim kho cov ntshav khiav thiab txhawb nqa cov pa oxygen, uas tuaj yeem ua kom lub hlwb tau txais cov khoom noj txaus thiab lub zog, yog li txhim kho lub hlwb tseem ceeb thiab kev ua siab ntev.

Nyem paub ntxiv los txhim kho kev nco

Qhov sib txuam ntawm -SYN hauv PD qhia tias qhov tsis ua haujlwm ntawm chaperone-mediated autophagy (CMA), ib qho tseem ceeb rau kev ua haujlwm ntawm autophagic degradation ntawm -SYN [155].

Kev hloov pauv hauv ntau lub autophagyreceptors, suav nrog SQSTM1 / p62 [155], OPTN, thiab UBQLN2, tau cuam tshuam nrog cov kab mob ntawm ALS [156–158]. Kev koom tes ntawm DDR thiab autophagy raws li qhov ncaj qha ntawm NDDs tseem tsis tau tsim muaj txiaj ntsig zoo, txawm hais tias cov ntaub ntawv qhia txog kev sib txuas ncaj qha ntawm DNA kho tshuab thiab autophagy los ntawm ntau yam, tsis muaj kev tshwj xeeb [159–161].

Kev ua kom ATM tuaj yeem ua rau autophagy induction los ntawm 50 AMPactivated protein kinase (AMPK) hauv cov lus teb rau ROS [162,163]. Thaum Atm-/- neurons qhia qhov txawv txav autophagy, ATM nws tus kheej yog ua tiav los ntawm autophagic degradation [164].Parp1 knockout nas raug mob rau kev tshaib plab tshwm sim tsis txaus siab autophagy, implying lub physiological lub luag hauj lwm rau PARP1 nyob rau hauv starvation-induced autophagy [165].

Qhov kev sib txuas ntawm DDR thiab autophagy zoo li bidirectional, raws li khob tawm BECLIN1, ib qho protein uas koom nrog hauv autophagy induction, txo cov haujlwm thiab theem ntawm HR thiab NHEJproteins tseem ceeb, thiab tseem txo qis qhov tsim ntawm DNA-PK complexes [166,167].

SQSTM1/p62 tau pom tias tswj qhov sib piv ntawm HR thiab NHEJ los ntawm kev txhawb nqa yav tom ntej uponradiation [168]. CMA tswj cov qib CHK1 thiab tiv thaiv cov hyperphosphorylation thiab tsis ruaj khov ntawm MRN complex [169]. Cov khoom txhais lus ntawm ultraviolet irradiationresistance-associated gene (UVRAG), ib qho tseem ceeb hauv kev pib autophagy, patrolsDSB kho kev ua haujlwm los ntawm kev khi ncaj qha rau DNA-PK hauv NHEJ [170].

Interestingly, DNAdamage tuaj yeem ntxias mitophagy, uas tuaj yeem ua lub luag haujlwm hauv kev tiv thaiv cov hlwb tiv thaiv DNA puas-vim cellular tuag [171]. Txawm hais tias tsis tau tshawb nrhiav rau DDR, peb pab pawg tsis ntev los no tau qhia txog qhov cuam tshuam ntawm endoplasmic stress (ER stress) kho kom muaj sia nyob autophagyafter hluav taws xob vim ROS induction [172].+

5.2. DDR thiab Neuroinflamation

Neuroinflamation yog lwm qhov tshwm sim tshwm sim hauv NDDs sib txawv. Lub voj voog dav dav ntseeg tau ua haujlwm, suav nrog neuroinflammation, oxidative stress, andneurodegeneration [173,174].

Kev mob tshwm sim tuaj yeem ua rau nws tus kheej ua rau muaj kev puas tsuaj DNA los ntawm kev tsim ntawm ROS thiab reactive nitrogen hom (RNS). Cov kab mob ua rau tsis yog tsuas yog mutagenic DNA lesions, xws li 8-nitroguanidine thiab 8-oxoG tab sis kuj cuam tshuam tsis zoo rau DNA kho lub peev xwm los ntawm inhibiting ntau yam tseem ceeb DNA kho enzymes [175,176].

Lub seminal nrhiav pom ntawm cyclic guanosine monophosphate-adenosine monophosphate (GMP-AMP) synthase (cGAS) raws li cov tsiaj txhu cytosolic DNA sensor los ntawm Sun et al. tau tsim kev sib txuas ncaj qha ntawm DNA puas thiab neuroinflamation [177].

Thaum bindingto cytosolic DNA, cGAS converts ATP thiab GTP rau cyclic GMP-AMP (cGMP), uas bindsand activates endoplasmic reticulum protein stimulator ntawm interferon noob (STING), thaum kawg inducing zus tau tej cov hom I interferons los ntawm transcription factorNF-kB thiab IRF3. [178].

Kev ua kom ntawm cGAS-STING tau pom nyob rau hauv ob peb NDDs: inan Atm-tsis muaj nas qauv nrog neuroinflammatory thiab neurodegenerative phenotypes, tsub zuj zuj ntawm cytosolic DNA ua rau txhim kho qib ntawm phosphorylated TBK1 (qhia ntawm STING activation) tau pom nyob rau hauv ntau hom cell, nrog rau microglia [179].

Xu et al. pom tau tias cGAMP tuaj yeem txwv AD los ntawm kev nce qib TREM2 [180]. IniPSC-derived ALS tus neeg mob lub cev muaj zog neurons, TDP-43 ua rau kev tso tawm ntawm mtDNA, ua rau cGAS-STING ua kom, thiab neuroinflammation tau pom [181].

Qhov induction ntawm IL6 nyob rau hauv cov lus teb rau circulating cell-free mtDNA tau raug tshaj tawm nyob rau hauv Parkinson cov neeg mob'serum [182]. Li no, cGAS-STING-mediated o tshwm sim los ua lwm tus yam ntxwv ntawm NDDs.

Hauv cov ntsiab lus, ib tus neeg DDR cov proteins tuaj yeem koom nrog ntau tshaj ib NDD (Daim duab 2) thiab tuaj yeem ua rau muaj kev cuam tshuam ntawm neurodegenerative los ntawm lawv cov kev cuam tshuam nrog ntau cov txheej txheem ntawm tes (Daim duab 3).

6. Cov Qauv Txheej Txheem los Kawm NDDs thiab Kev Kho Mob

Txawm hais tias cov ntaub so ntswg tom qab lub hlwb muaj txiaj ntsig zoo rau kev kos duab loj lossis cov qauv molecular txawv hauv DDR cov cim nyob rau theem kawg ntawm NDDs, nws tsis muaj zog los piav qhia cov kab mob.

Yog li, tsiaj cov qauv tseem yog cov cuab yeej tseem ceeb los kawm txog cov txheej txheem tsav tsheb neurodegeneration hauv kev xav txog lub neej. Kev xaiv ntawm cov kev tshawb fawb txuas DDR rau NDDs siv ntau yam qauv kev sib tham saum toj no lossis qhia cov qauv tsim nyog los kawm txog qhov crosstalk no tau sau tseg hauv Table 1.

Raws li muaj pov thawj los ntawm cov kev sib tham saum toj no, rodentsremain feem ntau siv cov qauv tsiaj. Rau AD, piv txwv li, muaj ntau tshaj li ob puas tus qauv nas sib txawv (https://www.alzforum.org/research-models/search (mus txog 19 Lub Ob Hlis 2021)).

Txawm li cas los xij, tsis muaj tus qauv rov hais dua tag nrho cov cardinalphenotypes pom hauv tib neeg cov kab mob, qhia txog qhov xav tau cov qauv zoo dua rau tus qauv NDDs.

Invertebrate tsiaj kuj pheej yig los tswj thiab muaj lub neej luv luv thiab rov ua dua tshiab. Cov khoom no ua rau cov qauv uas tsis yog vertebrate amenable rau tshuaj thiab tshuaj ntsuam genetic.

Lub nematode Caenorhabditis elegans (C. elegans) yog ib qho piv txwv ntawm tus tsiaj uas nws lub cev pob tshab tso cai rau kev saib xyuas ntawm neurodegeneration hauv vivo.Humanized tsiaj qauv muaj nyob rau hauv uas cov tsiaj transgenic qhia tib neeg -SYN [187,188], A 1-42, TAU [189,190 ], TDP-43, and SOD1 [191–193].

Qhov muaj nyob ntawm kev soj ntsuam tus cwj pwm ua rau nws muaj peev xwm kawm txog kev muaj peev xwm thiab kev ua haujlwm ntawm tus kheej neurons thaum lub sijhawm ua neej nyob. Yog li ntawd, cov tsiaj yooj yim muab txoj hauv kev zoo los kawm txog kev sib koom ua ke ntawm caj ces thiab ib puag ncig kev pheej hmoo ua ke nrog kev laus, qhov tseem ceeb tshaj plaws rau NDD.

Txog kev koom tes ntawm DDR, C. elegans muaj tsawg dua ntawm DNA kho cov noob, ua rau nws yog ib qho cuab yeej zoo los txiav txim seb thiab yuav ua li cas DNA kho cov proteins cuam tshuam rau neurodegeneration. Ib qho kev txwv ntawm C. elegans yog tias nws tsis muaj lub hlwb. Yog li, cov qauv vertebrate yog xav tau. Ntawm cov no, Danio rerio (D. rerio) tau nrov zuj zus vim nws muaj vasculature thiab lub hlwb sib cais los ntawm ntshav-hlwb barrier [194–196].

Txoj kev loj hlob ntawm tib neeg iPSC thev naus laus zis tau qhib qhov rooj rau kev ua qauv ntawm cov kab mob hauv lub hlwb. Cov txheej txheem tsim muaj muaj los tsim ntau hom hlwb hlwb los ntawm tus neeg mob tau txais iPSCs hauv ob-dimensional (2D) monolayer kab lis kev cai thiab siv cov qauv no AD [197,198], ALS [199–201], thiab PD [202,203].

Qhov muaj peev xwm ntawm kev qhia txog kev kho genome hauv iPSCs (piv txwv li, ntawm CRISPR/CAS9) ntxiv kom muaj peev xwm ntawm cov cell no los kawm txog lub luag haujlwm tshwj xeeb ntawm cov noob caj noob ces. Tsis tas li ntawd, lub luag haujlwm ntawm lwm hom hlwb hlwb (xws li glial hlwb, kuj tau muab los ntawm iPSCs) tuaj yeem kawm hauv cov txheej txheem kev coj noj coj ua tsis ntev los no [204].

Tseem, 2D kab lis kev cai kab lis kev cai tsis rov hais dua qhov nyuaj ntawm lub hlwb, thiab cov phenotypes xws li kev sib txuas ntawm cov protein sib txuas yog qhov nyuaj rau kev soj ntsuam. Yog li, 2D iPSCs tsis yog qhov kev xaiv tshaj plaws los ua qauv NDDs.

Kev koom tes ntawm tus kheej ntawm lub cev embryoid los ntawm iPSCs, hu ua 3D-organoid qauv, tuaj yeem tso cai rau peb los kawm txog kev loj hlob ntawm tes thiab kev sib cuam tshuam ntawm tes hauv 3D humanbrain microenvironment [205].

Kev nce qib hauv 3D-kev coj noj coj ua tau ua rau muaj ntau hom hlwb hlwb thiab lub hlwb tshwj xeeb hauv cov organoids (mini-brains) [206].Forebrain cortical organoids, mid-brain organoids, thiab motor neuron spheroids derivedfrom AD thiab HD, PD. , thiab ALS tus neeg mob iPSCs, ntsig txog, tuaj yeem qhia cov phenotypes cardinaltisue thiab tuaj yeem, yog li, muaj txiaj ntsig zoo rau kev nkag siab cov NDDs nyuaj no (Daim duab 4) [207–213].

Daim duab 4. Lub peev xwm ntawm 2D iPSCs thiab 3D-organoids ua qauv NDDs. Cov tawv nqaij fibroblasts muab los ntawm NDD cov neeg mob tuaj yeem ua haujlwm rau hauv iPSCs. Cov iPSCs no tuaj yeem sib txawv rau ntau hom hlwb hlwb xws li ntau hom neuron, microglia, thiab lwm yam.

iPSC-derived 3D-organoids muaj feem ntau ntawm cov hlwb hlwb (tshwj tsis yog microglia thiab vasculature, uas tuaj yeem ua ke nrog 3D-organoids) thiab tuaj yeem pom cov kab mob loj. Ntau yam kev siv ntawm cov qauv no kuj tau pom. Tsim nrog BioRender.com.

7. Cov lus xaus

Txhawm rau xaus, ob qho tib si antioxidant tiv thaiv thiab kho DNA tiv thaiv kev sib sau ntawm DNA puas thiab yog li tiv thaiv kev txhim kho ntawm NDDs. Ib qho piv txwv ntawm kev tiv thaiv antioxidant yog scavenger superoxide dismutase1 (SOD1) uas tiv thaiv neuronsagainst amyloid (A) mediated neurotoxicity [214]. Ob qho kev tshaj tawm ntawm cov tsiaj qus-typeSOD1 thiab kev hloov pauv hauv SOD1 yog txuam nrog ntau lub hnub nyoog ntsig txog NDDs [11,215,216].

Ntau qhov kev sim tshuaj yog tsom rau hom tsiaj qus SOD1 lossis mutant SOD1 los tiv thaiv kev sib sau ua ke thiab kev ua tsis zoo hauv NDDs, thiab tam sim no muaj cov tshuaj tiv thaiv oligonucleotide nyob rau theem III kev sim tshuaj (NCT02623699).

Ib qho me me molecule, Arimoclomol, uas txhawb nqa qhov ua kom zoo ntawm SOD1 hauv endoplasmic reticulum (ER) [11], yog nyob rau theem III sim (NCT03491462).Txawm hais tias lub hom phiaj kho DNA lossis DDR tuaj yeem tsim kho rau hauv kev xaiv kho mob tiv thaiv NDDs tseem yuav yog. qhia meej.

Txawm li cas los xij, qhov tshwm sim ntawm PARP1 ua kom los ntawm SSBas ib qho kev tshawb pom hauv NDDs thiab muaj PARP1 inhibitors qhia tias qhov no yuav yog txoj hauv kev mus nrhiav. Txawm li cas los xij, ncaj qha kev tsom mus rau PARP1 muaj kev pheej hmoo ntawm kev tshem tawm cov txiaj ntsig ntawm lwm lub hlwb thiab cov ntaub so ntswg. Ib qho txiaj ntsig ntawm PARP1 overactivation yog depletion ntawm cellular NAD +, uas yog substrate ntawm PARP1.

Hauv peb txoj haujlwm dhau los, peb tau qhia tias kev txhawb nqa NAD + qib yog ib lub tswv yim zoo los txhawb kev kho DNA thiab tiv thaiv cov kab mob neurodegeneration hauv cov kab mob tsis tshua muaj DNA kho [140,146,184]. Txhawm rau tshawb nrhiav kev kho mob muaj peev xwm ntawm DDR, cov kev tshawb fawb hla hom uas sib txawv cov qauv sib xyaw ua ke kom rov sau dua cov kev sib txawv ntawm cov kab mob nyuaj no tuaj yeem siv tau.

iPSC-derived 3D-organoid qauv tshwm sim raws li cov qauv kev cog lus uas tuaj yeem ntes qhov nyuaj ntawm DDR thiab nws cov lus sib tham nrog lwm cov txheej txheem ntawm tes tseem ceeb rau kev tswj hwm kev noj qab haus huv.

Sau Kev Koom Tes: Kev Tsim Nyog, HN thiab KS; methodology, SG; software, PY, TS, and K.S.; validation, SG, PY, TS, HN, and KS; kev soj ntsuam, SG; kev tshawb nrhiav, SG; Resources, HN thiab KS; data curation, SG, PY, TS, and KS; sau-original kev npaj, SG, PY, TS, HN, thiab KS; sau-review and editing, SG, PY, TS, HN, and KS; visualization, SG, HN, thiab KS; saib xyuas, HN, thiab KS; kev tswj xyuas qhov project, SG, HN, thiab KS; kev nrhiav nyiaj txiag, HN Txhua tus kws sau ntawv tau nyeem thiab pom zoo rau cov ntawv luam tawm ntawm cov ntawv sau.

Cov Nyiaj Txiag: Qhov kev tshawb fawb no tau txais nyiaj los ntawm South East Regional Health Authority (Project no. 279922and 2017029) thiab Norwegian Research Council (Grant no. 302483).

Institutional Review Board Statement: Tsis siv tau.

Cov Lus Qhia Txog Kev Pom Zoo: Tsis siv tau.

Cov Lus Qhia Txog Cov Ntaub Ntawv: Tsis muaj cov ntaub ntawv tshiab raug tsim lossis tshuaj xyuas hauv qhov kev tshawb fawb no. Kev sib faib cov ntaub ntawv tsis siv rau kab lus no.

Kev lees paub: Peb lees paub Ellen Tenstad @ScienceShaped, Carina Knudson, thiab FranciscoJosé Naranjo Galindo rau kev pab nrog cov duab kos duab thiab Evandro Fei Fang, Diana L. Bordin, thiab Lisa Lirussi rau kev nyeem ntawv tseem ceeb ntawm cov ntawv sau.

SG thiab PY tau txais nyiaj los ntawm kev pab nyiaj los ntawm South East Regional Health Authority (Project no. 279922 thiab 2017029) thiab TSG tau txais nyiaj los ntawm agrant los ntawm Norwegian Research Council (Grant no. 302483).

Kev tsis sib haum xeeb ntawm kev txaus siab: Peb lees paub tias txhua tus kws sau ntawv tsis muaj kev tsis sib haum xeeb ntawm cov ntawv sau no.

Cov ntaub ntawv

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11. Trist, BG; Davies, KM; Koob, V.; Genoud, S.; Ortega, R. Roudeau, S.; Carmona, UA; De Silva, K.; Wasinger, V.; Lewis, SJG; et al. Amyotrophic lateral sclerosis-zoo li superoxide dismutase 1 proteinopathy yog txuam nrog neuronal poob hauv Parkinson's disease hlwb. Acta Neuropathol. 2017, 134, 113–127. [CrossRef]

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