Macroautophagy Thiab Mitophagy nyob rau hauv Neurodegenerative Disorders: Tsom Rau Kev Kho Mob Ntu 5

CMA kuj yog lub luag haujlwm tswj hwm cov theem ntawm haiv neeg aSyn. Ib tug fascinatingstudy qhia tau hais tias cov tsiaj overexpressing WT aSyn tau txais ib tug stereotaxic txhaj ntawm lentiviral LAMP2a tso tawm siab CMA kev ua ub no concomitant nrog txo qis ntawm endogenous aSyn tshaj cov nas tsis kho [380]. MicroRNAs (miRNAs) tuaj yeem hloov kho CMA cov xwm txheej.

Kev sib raug zoo ntawm CMA thiab lub cim xeeb yog ze ze. CMA yog cov ntawv luv ntawm Certified Management Accountant, uas yog daim ntawv pov thawj kev tswj hwm nyiaj txiag kev tsim nyog tau lees paub thoob ntiaj teb. Kev nco yog lub peev xwm ntawm tib neeg lub hlwb, uas yog lub peev xwm nco qab, khaws cia, thiab nco qab cov ntaub ntawv.

Hauv cov txheej txheem ntawm kev npaj rau CMA, qhov tseem ceeb ntawm kev nco tsis tuaj yeem tsis quav ntsej. Qhov kev xeem CMA muaj ntau lub tswv yim, kev paub, thiab kev txawj ntse, uas xav kom cov neeg sib tw siv lub zog thiab lub sijhawm los kawm thiab nkag siab, thiab kev nco zoo cuam tshuam ncaj qha rau kev kawm thiab cov qhab nia xeem.

Feem ntau hais lus, cov neeg uas muaj lub cim xeeb muaj zog yog qhov tsim nyog rau kev kuaj CMA. Vim tias lawv tuaj yeem paub cov ntsiab lus paub sai dua, nco qab cov qauv thiab cov ntsiab lus yooj yim dua, thiab teb cov lus nug tau yooj yim dua. Cov neeg uas tsis nco qab xav tau ntau lub sijhawm thiab lub zog los tshuaj xyuas thiab kawm kom paub tseeb tias lawv cov kev paub paub thiab cov qhab nia xeem.

Txawm li cas los xij, kev nco tsis zoo li qub, thiab peb tuaj yeem txhim kho kev nco los ntawm kev cob qhia thiab kev tawm dag zog. Piv txwv li, kev nco tuaj yeem txhim kho los ntawm kev kawm los ntawm ntau qhov kev nkag siab, kev kawm rov ua dua, kev xyaum ua kom tawg, thiab siv kev kawm. Tsuav yog muaj kev ntseeg siab thiab ua siab ntev, txhua tus tuaj yeem txhim kho lawv lub cim xeeb thiab zoo dua nrog CMA kev xeem.

Hauv luv luv, CMA yog ze ze rau kev nco. Peb yuav tsum paub txog qhov tseem ceeb ntawm kev nco thiab nquag siv txoj hauv kev zoo los txhim kho kev nco, ua lub hauv paus rau kev npaj zoo dua thiab dhau qhov kev xeem CMA. Chengman:

Nws tuaj yeem pom tias peb yuav tsum txhim kho kev nco. Cistanche tuaj yeem txhim kho kev nco zoo vim Cistanche yog cov tshuaj suav tshuaj suav nrog ntau yam tshwj xeeb, ib qho ntawm kev txhim kho kev nco. Cov nyhuv ntawm Cistanche yog los ntawm ntau yam khoom xyaw uas nws muaj, nrog rau tannic acid, polysaccharides, flavonoid glycosides, thiab lwm yam. Cov khoom xyaw no tuaj yeem txhawb lub hlwb kev noj qab haus huv ntau txoj hauv kev.

Nyem Paub Txoj Kev Txhim Kho Kev Nco

Interestingly, miRNAs miR-26b, miR-106a, miR-301b thiab miR-21, miR-224, thiab miR-373, heev qhia hauv SNpc ntawm PD cov neeg mob, yog txuam nrog txo qis ntawm Hsc70 thiab LAMP2a, feem [381].

Tsis tas li ntawd, kev hloov pauv ntawm CMA los ntawm kev siv geniposide tau ua kom pom cov txiaj ntsig zoo hauv kev cawm dopaminergicneurodegeneration hauv MPTP-induced nas qauv los ntawm kev nce LAMP2a expressionand txo cov theem ntawm endogenous aSyn los ntawm inhibition ntawm miR-21 [382].

Hais txog cov kev soj ntsuam no, peb tuaj yeem txaus siab tias autophagy ib txwm muaj kev ua haujlwm tsis zoo hauv PD vim tias nws tuaj yeem tshem tawm cov teeb meem hauv cellular tseem ceeb tshwm sim hauv cov kab mob neurons thaum mus ze.

Yog li ntawd, kev kho tshuaj kho mob orgene therapy uas pab txhawb mitochondrial degradation zoo li yog nyob rau hauv pem hauv ntej ntawm kab mob-hloov kho kev kho mob PD los yog tsawg kawg yog txwv tsis pub tus kab mob, uas yog tseem ceeb heev txij li thaum tseem tsis tau muaj kev kho mob zoo (Daim duab 5).

4.3. Targeting Macroautophagy thiab Mitophagy hauv HD

Xav txog lub luag haujlwm tseem ceeb ntawm autophagy hauv kev tshem tawm mHTT, txoj kev tshawb fawb kho mob ntawm cov txheej txheem no hauv HD yog pom tseeb. Pharmacological lossis genetic therapeutic manipulation of autophagy hauv vivo tau qhia tau zoo heev hauv cov qauv tsiaj ntawm HD, nrog rau kev txhim kho kev coj tus cwj pwm txawv txav thiab neuropathology.

Qee cov tshuaj pom zoo, xws li rapamycin, cimetidine, thiab spermidine, yog cov autophagy inducers zoo thiab tau siv hauv cov kev sim no. Tsis ntev los no, txo HTT qhia los ntawm DNA kho, siRNAs, shRNAs, los yog antisense oligonucleotides genetic le caag tau sim nrog rau kev kho tshuaj pharmacological kom txo qis mHTT protein ntau ntau.

Ravikumar thiab cov npoj yaig tau pom tias qhov kev ua haujlwm ntawm autophagy los ntawm rapamycin, amTOR inhibitor, muaj cov teebmeem neuroprotective thiab attenuated HTT toxicity hauv tus qauv ya ntawm HD [271].

Tsis tas li ntawd, mTOR inhibitor, CCI-779, rapamycin analog, txhim kho motorphenotypes hauv HD transgenic HD-N171-N82Q nas thiab txo polyQ-HTT aggregateload los ntawm inducing autophagy activation [262]. Txawm li cas los xij, cov kev tshawb fawb tsis ntev los no tau pom tias kev kho dua tshiab ntawm mTORC1 kev ua tau zoo txhim kho lub cev muaj zog thiab lub hlwb pathology hauv N171-82Q HD nas [383].

Tsis tas li ntawd, mTORC1 kev ua haujlwm tau txo qis hauv cov neeg mob HD thiab tseem nyob hauv striatum ntawm HD nas qauv.Rilmenidine, ib qho mTOR-ywj siab macroautophagy inducer, txo qis cov theem ntawm cov teeb meem mHTT tawg thiab txhim kho lub cev muaj zog phenotypes hauv tib HD mousemodel [384].

Tsis tas li ntawd, HD R6 / 2 transgenic nas kho nrog trehalose, ib qho kev tsis txaus ntseeg tau qhia rau induce macroautophagy, nthuav tawm cov tshuaj lom, txhim kho lub cev muaj zog, thiab txuas ntxiv lub neej [385].

HD tus neeg mob fibroblasts kho nrog trehalose pom tau tias muaj kev hloov pauv ntawm cov neurodegenerative phenotypes tshwm sim los ntawm UPS inhibition [386]. Lithium, uas txo IP3 qib, tau pom tias pab kom meej meej mHTT hauv drosophila HD qauv [354]. Berberine, uas tuaj yeem ua rau autophagy ntawm AMPK ua kom, ntxiv rau qhov ua tau zoo hauv N171-82QHD nas qauv [387].

Clonidine, tus modulator ntawm cAMP los yog IP3 rau induce autophagy, isanother autophagy-related molecule can ameliorate phenotypes in mammalian cells, yoov, thiab zebrafish HD qauv [388].

Calpain tuaj yeem yog lub hom phiaj rau kev nce autophagicflux ntawm mHTT; Qhov tseeb, kev poob qis ntawm calpain tau pom tias txo qis mHTT lub nra hnyav hauv HD Drosophila tus qauv, thiab cov txiaj ntsig zoo sib xws tau pom hauv transgenic N171-82Qmice, uas overexpressed calpastatin (CAST), endogenous inhibitor ntawm calpain [389].

Pramipexole, ib tug dopamine receptor agonist, muaj peev xwm ua kom autophagy tej zaum yog los ntawm modulating cAMP signaling pathways nyob rau hauv lub R6/1 HD nas qauv, txo solublemHTT theem [390].

Tsis tas li ntawd, STHdhQ111/Q111 hlwb [391] thiab 109Q/109Q nas striatalcells [392] kho nrog metformin (ib qho AMPK activating inducer ntawm autophagy, raws li tau piav ua ntej hauv qhov kev tshuaj xyuas no) txo qis mHTT-txuas nrog cytotoxicity.

Metformin yog siv los kho mob ntshav qab zib hom II, thiab HD cov neeg mob uas tau saib xyuas hauv Kev Tshawb Fawb-HD (kev soj ntsuam thoob ntiaj teb thiab kev kawm ntev ntev ntawm HD cov neeg mob) thiab twb tau noj metformin tau pom tias muaj kev paub zoo dua qub thaum piv rau cov neeg mob uas tsis muaj metformin-chaw [393]. Kev siv Akt inhibitor 10-[40-(N-diethylamino)butyl]-2-chlorophenoxazine (10-NCP) kuj txo mHTT aggregates nyob rau hauv HD nas striatumand txo striatal neuronal. tuag [394].

Tsis ntev los no, Siddiqi thiab cov npoj yaig tau pom tias HDN171-82Q nas tau kho nrog felodipine, tshuaj tiv thaiv kab mob siab, tau nthuav tawm cov yam ntxwv zoo nrog cov tshuaj pharmacokinetics zoo ib yam li nws cov kev siv tsis zoo rau tib neeg [395].

Qhov ua tau zoo ntawm qee qhov me me molecules rau lub hom phiaj tib txoj hauv kev hauv vivohas tseem tsis tau lees paub. Yog li, kev siv cov kev kho mob sib xyaw ua ke rau kev txo qis mHTT-kev cuam tshuam toxicity, uas ib txhij upregulates autophagy los ntawm ob qho tib si mTORindependent thiab -dependent txoj kev, zoo li yuav txaus siab heev.

Tseeb tiag, HD qauv kev kho mob sib xyaw ua ke, xws li trehalose-rapamycin [396] lossis lithium-rapamycin [354], tau pom cov txiaj ntsig zoo. Tsis tas li ntawd, lwm lub tswv yim yog tswj hwm cov haujlwm ntawm qhov pib ntawm tus mob autophagy los ntawm ULK1 complex.

WT ULK1 overexpression txo qis mHTT qib hauv cov kab ntawm tes, qhia tias ULK1 kinase kev ua haujlwm yog ib qho kev txwv rau kev tshem tawm autophagic ntawm mHTT [269].

Yog li, kev hloov pauv hauv mHTT load vim kev hloov pauv ntawm ULK1 kev ua haujlwm yog qhov kev xav zoo siab uas tam sim no muaj peev xwm sim nrog kev txhim kho tsis ntev los no ntawm ULK1 activators [326] thiab inhibitors [397].Lowering mHTT ntau ntau thiab toxicity tau raug ntawm ntau qhov kev tshawb fawb tsis ntev los no. .

Tseeb, nce mHTT xaiv autophagy tuaj yeem yog lub tswv yim zoo rau kev tshem tawm mHTT, uas tuaj yeem ncav cuag los ntawm kev nce mHTT cov khoom xa tuaj, thiab txheeb xyuas cov khoom sib txuas uas khaws cia mHTT hauv autophagy degradation system.

Tsis ntev los no, Li thiab cov npoj yaig tau ua qhov kev tshuaj ntsuam tsis pom zoo thiab txheeb xyuas plaub qhov sib txuas ntawm mHTT-LC3 txuas, tuaj yeem txuas mHTT rau autophagosome rau kev tshem tawm allele-xaiv ntawm mHTT [398].

Tsis tas li ntawd, Hodges thiab cov npoj yaig tau pom tias qib ntawm cov khoom siv protein ntau OPTN tau txo qis hauv caudate nucleus ntawm HD cov neeg mob, qhia tias qhov kev xaiv ntawm cov proteins sib xyaw tuaj yeem raug xaiv txo qis [399]. Yog li, augmentingcargo paub los ntawm adapter proteins, tejzaum nws los ntawm posttranslational hloov, tej zaum yuav yog ib tug nthuav HD kho txoj kev.

Raws li tau piav qhia ua ntej, CMA tuaj yeem nyiam lub hom phiaj soluble, N-terminal fragments ofpolyQ-HTT. Txij li cov ntaub ntawv luv luv ntawm mHTT, uas yog cytotoxic, muaj nyob rau hauv lub hlwb ntawm HD cov neeg mob thiab HD tsiaj cov qauv, cov kev xaiv degradation ntawm cov ntaub ntawv truncated los ntawm CMA tej zaum yuav sawv cev rau ib tug kho lub sij hawm nyob rau hauv HD.

Tseeb tiag, cytosolic chaperoneHsc70 tuaj yeem khi thiab xa ncaj qha mHTT mus rau lysosome ntawm CMA, ua rau xaiv degradation ntawm mHTT thiab txo toxicity hauv HD nas [400] thiab ya qauv [401].

Concordantly, Hsp70 knockout aggravated lub cev muaj zog cov tsos mob nyob rau hauv lub R6/2 HD nas [402], whereas lub phytocompound azadiradione nce qhov kev qhia ntawm Hsp70, uas ua rau txo polyQ aggregates thiab cawm ntawm ommatidia morphology nyob rau hauv Drosophilaeyes [403]. Ntxiv mus, R6 / 2 HD nas siv CMA-targeting adapter molecule tawm tsampolyQ-HTT pom tus kab mob ameliorated phenotype [400].

Txij li thaum muaj kev lees paub tsis ua tiav thaum qhov kev qhia ntawm mHTT tshwm sim, vim yog lub cev sib cuam tshuam ntawm HTT nrog p62 thiab ULK1 cov proteins, nws tau tshaj tawm tias mHTT tuaj yeem cuam tshuam kev xa khoom ntawm tus chij tsis ua haujlwm mitochondria rau formautophagosomes. Txoj kev PINK1/Parkin-dependent mitophagy txoj kev yog txoj hauv kev zoo tshaj plaws mitophagy; Txawm li cas los xij, PINK1 / Parkin-independent mitophagy kuj tshwm sim [404].

Raws li tau piav qhia yav dhau los, HTT ib txwm yog cov protein tseem ceeb hauv kev tswj hwm ntawm autophagosome dynamics, nrog rau kev yos hav zoov cov protein 1 (HAP1), los ntawm kev tswj hwm ntawm dynein thiab kinesin. Interestingly, impaired axonal thauj thiab maturation ntawm autophagosomes nyob rau hauv lub xub ntiag ntawm mHTT muaj feem xyuam rau inefficient mitochondrial degradation [265].

Cov txiaj ntsig no qhia tias ua rau muaj kev puas tsuaj ntawm mitochondria puas thiab nyiam mitochondrial biogenesis yog qhov tseem ceeb rau kev kho mob HD (Daim duab 6).

5. Cov lus xaus

Kev sib sau ntawm cov tshuaj lom hauv cov cellular protein aggregates (piv txwv li, oligomers) yog ib qho cim ntawm ntau yam kab mob neurodegenerative, suav nrog AD, PD, thiab HD, thiab ntseeg tau tias ua lub luag haujlwm tsis zoo hauv kev ua haujlwm proteostasis thiab organelle.

Autophagy tuaj yeem tsim txoj hauv kev tseem ceeb rau kev tshem tawm cov kab mob sib xyaw ua ke los yog tuaj yeem raug cuam tshuam raws li kev tshem tawm cov txheej txheem thaum lwm cov txheej txheem protein degradation ua tsis tiav thaum kis kab mob.

Txawm li cas los xij, kev kho cov protein ntau-txo qis tsis tshua muaj kev txo qis cov tsos mob hauv cov qauv kab mob sib txawv, hais txog tias kev siv zog rau kev xaiv autophagy-raws li kev kho mob tsom rau autophagic flux restoration, txhim kho kev ua haujlwm ntawm lysosomal, thiab / lossis kev xaiv hauv cov khoom xa tuaj rau autophagic clearance.

Tseeb, nyob rau hauv lub xyoo tas los no, ib tug tseem ceeb nce nyob rau hauv autophagy-targeted tshuaj txoj kev loj hlob tau raug soj ntsuam, feem ntau yog vim muaj kev txhim kho kev paub ntawm lub mechanism thiab kev tswj ntawm autophagy nyob rau hauv txawv tib neeg kab mob. Txawm hais tias tag nrho cov tswv yim kho mob ua ntej, yuav tsum tau ceev faj thaum soj ntsuam cov txiaj ntsig ntawm autophagy modulators inneurodegenerative mob.

Txawm hais tias autophagy yog ib qho kev kawm zoo ntawm qib biochemical thiab cellular, nws lub luag haujlwm tseem ceeb hauv neurodegeneration thiab kab mob kev loj hlob yog deb ntawm kev nkag siab. Tseeb, muaj qee qhov tsis sib xws tau tshaj tawm hauv cov qauv kab mob sib txawv thiab / lossis cov kab mob sib txawv. Hauv PD, piv txwv li, qhov pib nce hauv cov txheej txheem autophagic tau pom nyob rau theem pib, thaum cov qauv tom qab tuag taw qhia qhov sib txawv.

Txawm hais tias qhov no yuav zoo li tsis sib haum xeeb, qhov tseeb tias ntau cov autophagic proteins feem ntau colocalize nyob rau hauv lub aSyn deposits qhia tias cov txheej txheem autophagic pib ua hauj lwm nyob rau hauv ib tug twb tsim pathological lub xeev thiab decays thoob plaws hauv lub kev loj hlob ntawm tus kab mob. Nyob ntawm seb qhov chaw kho mob cov ntsiab lus, induction los yog suppression ntawm autophagy tej zaum yuav tshwm sim. ib txoj kev kho mob tau.

Ib txoj hauv kev zoo sib xws tuaj yeem siv rau mitophagy, txoj hauv kev tseem ceeb ntawm kev tswj xyuas kev ua haujlwm zoo rau kev tshem tawm cov laus thiab tsis zoo mitochondria los ntawm lysosomal hydrolysis. Xav txog tias mitochondrial dysfunctionis feem ntau koom nrog hauv kev ua haujlwm tsis zoo ntawm lub paj hlwb, kev tiv thaiv kev ua haujlwm mitochondrial los ntawm kev txhim kho mitophagy kom muaj kev noj qab haus huv mitochondrial cov pejxeem hauv cov neurons tej zaum yuav yog ib qho zoo tshaj plaws los txhawb kev tiv thaiv kab mob thiab kho cov kab mob ntsig txog kab mob (Table 1).

Txawm hais tias mitophagy-txog molecular thiab cellular mechanisms tau kawm ntau nyob rau hauv kaum xyoo dhau los, mitophagy txawv txav tsuas yog tau lees paub tsis ntev los no tias yog ib tus neeg tseem ceeb koom nrog hauv neurodegeneration. Kev tshawb fawb ntawm cov xwm txheej mitophagy, nrog rau cov txheej txheem ntxaws ntxaws, yog qhov tseem ceeb rau kev nkag siab zoo dua nws lub luag haujlwm hauv cov kab mob pathogenesis.

Piv txwv li, kev ua kom Parkin txhawm rau txhim kho mitophagy tuaj yeem yog lub tswv yim zoo. Tsis tas li ntawd, cov kws tshuaj muaj peev xwm ua rau muaj kev cuam tshuam mitophagyto txhawb kev tshem tawm ntawm mitochondria puas tuaj yeem yog lub tswv yim zoo rau kev ua tiav cov txiaj ntsig kho mob tseem ceeb. Tseeb tiag, cov tswv yim los txhawb cov mitophagy los ntawm kev txhim kho me ntsis bioenergetic kev nyuaj siab los yog inhibiting mTOR kev ua ub no kuj tau ua pov thawj tias muaj txiaj ntsig zoo hauv kev ncua lossis kho cov kab mob neurodegenerative.

Txog niaj hnub no, muaj kev tshawb fawb tsawg heev uas qhia txog qhov cuam tshuam txog kev kho mob thaum autophagy raug hloov kho raws li kev kho mob rau cov kab mob loj zuj zus thiab puas tsuaj. Txawm li cas los xij, cov kev tshawb fawb tseem ceeb thiab preclinical qhia tias cov modulators ntawm autophagy tsim ib qho kev cog lus kho zoo raws li cov txheej txheem tau raug tshem tawm hauv cov ntsiab lus ntawm cov kab mob neurodegenerative.

Qhov tsis muaj autophagy ntsig txog biomarker uas tuaj yeem siv los ntsuas qhov kev kho mob ua haujlwm ntawm autophagy-modulating tus neeg saib xyuas lossis tus qauv txheej txheem los ntsuas autophagy hauv vivo, ntawm lwm yam tsis paub, tau ncua kev txhim kho kev kho mob.

Lub xyoo tom ntej no tau cia siab tias yuav txhawb nqa qhov laj thawj rau kev tshawb nrhiav, tshuaj xyuas, thiab cov yam ntxwv tshiab autophagy-targeting cov tshuaj raws li cov tswv yim kho mob hauv AD, PD, thiab HD, raws li kev paub ntau ntxiv tau sau txog cov txheej txheem tswj hwm thiab cov qauv tsim ntawm cov hom phiaj tseem ceeb uas tswj autophagy.

Kev tsim qauv ntawm selectivemodulators ntawm autophagy los yog repurposing ntawm cov tshuaj uas tej zaum yuav tshwj xeeb cov hom phiaj tseem ceeb autophagy intermediates yuav ua rau kom cov kev kho mob zoo tshaj plaws thiab txo cov kev mob tshwm sim. Noveltherapeutic agents thiab genetic-based methodologies targeting autophagy yuav sai sai no tawm tswv yim kho mob rau cov kab mob neurodegenerative.

Sau Cov Kev Pabcuam: Sau-tsim daim ntawv npaj: JDM, LF, RV; sau-saib xyuas thiab hloov kho: SMC, ACR; Kev saib xyuas: SMC, ACR; Kev nrhiav nyiaj txiag: SMC, ACR Txhua tus neeg sau ntawv tau nyeem thiab pom zoo rau cov ntawv luam tawm ntawm cov ntawv sau.

Cov Nyiaj Txiag: Txoj haujlwm no tau txais nyiaj los ntawm European Regional Development Fund (ERDF), dhau los ntawm Centro 2020 Regional Operational Program: project CENTRO-01-0145-FEDER-000012-HealthyAging2020 thiab los ntawm COMPETE 2020-Kev Ua Haujlwm Kev Ua Haujlwm rau Kev Sib Tw thiab Internationalization thiab Portuguese cov peev nyiaj los ntawm FCT-Fundação para a Ciência ea Tecnologia, nyob rau hauv cov haujlwm POCI-01-0145-FEDER-032316, POCI-01-0145-FEDER-029621, POCI-01-0145- FEDER030712, PTDC/MED-NEU/3644/2020 thiab UIDB/04539/2020. JDM thiab LF tau txais kev txhawb nqa los ntawm SFRH / BD / 146409 / 2019 thiab SFRH / BD / 148263 / 2019 FCT PhD kev sib raug zoo, raws li.

Institutional Review Board Statement: Tsis siv tau.

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

Cov Lus Qhia Muaj Cov Ntaub Ntawv: Tsis siv tau.

Kev tsis sib haum xeeb ntawm cov paj laum: Cov neeg sau ntawv tshaj tawm tsis muaj kev sib tw nyiaj txiag txaus siab lossis kev tsis sib haum xeeb ntawm kev txaus siab.

Cov ntaub ntawv

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