Neuroglial Senescence, -Synucleinopathy, Thiab Therapeutic Potential Of Senolytics hauv Parkinson's Disease Part 3

Hais txog PD pathology, activated caspase-1 cleaves synuclein rau hauv daim ntawv truncated uas yog heev yooj yim toforming insoluble aggregates yam ntxwv ntawm Lewy lub cev (Wang li al., 2016).

Thaum lawv muaj hnub nyoog, ntau tus neeg pom tias lawv lub cim xeeb pib poob qis. Qhov no tuaj yeem ua rau muaj ntau yam teeb meem, suav nrog lub sijhawm tsis nco qab, cov npe ntawm cov neeg nyob ze, thiab tseem ceeb hnub yug. Txawm li cas los xij, kev tshawb fawb tsis ntev los no qhia tias kev hloov pauv pathological cuam tshuam nrog PD (Parkinson tus kab mob) tuaj yeem muaj txiaj ntsig zoo rau kev nco.

PD yog tus kab mob neurodegenerative uas ua rau kev tuag ntawm cov neurons hauv ib cheeb tsam ntawm lub hlwb. Kev tuag nyob rau hauv cheeb tsam no tej zaum yuav muaj txim rau ntau yam ntawm kev txawj ntse muaj nuj nqi, tshwj xeeb tshaj yog nco. Txawm li cas los xij, kev hloov pauv pathological ntawm PD tuaj yeem muaj qee qhov txiaj ntsig zoo ntawm kev nco.

Hauv kev tshawb fawb PD, ib yam khoom hauv lub hlwb hu ua "Lewy cev" tau pom, uas yog cov qauv me me uas tsim los ntawm kev sib sau ua ke ntawm cov protein. Cov cev me me no feem ntau tshwm sim hauv lub hlwb ntawm cov neeg mob PD tab sis tsis ncaj qha ntsig txog cov teeb meem nco uas tshwm sim nyob rau theem pib thiab nruab nrab ntawm PD.

Kev tshawb fawb tsis ntev los no qhia tias Lewy lub cev hauv lub hlwb ntawm cov neeg mob PD tuaj yeem tiv thaiv lawv lub cim xeeb rau qee qhov. Tshwj xeeb tshaj yog nyob rau hauv cov nqe lus ntawm visuospatial nco, PD cov neeg mob yuav muaj qee yam kev tiv thaiv. Qhov no yog vim tias lub cev no qhib thiab txhim kho qee qhov chaw ntawm kev nco ua haujlwm. Txawm hais tias qhov kev tshawb fawb no tseem nyob hauv nws cov theem ua ntej, nws pom tseeb tias muaj kev sib txuas ntawm PD pathology thiab nco.

Zuag qhia tag nrho, txawm hais tias cov neeg mob PD tuaj yeem ntsib ntau yam teeb meem kev txawj ntse thiab lub neej, kev tshawb fawb qhia tias muaj Lewy lub cev hauv lub hlwb ntawm cov neeg mob PD tuaj yeem muaj kev cuam tshuam zoo rau kev nco txog visuospatial. Txawm hais tias txoj kev tshawb no tseem nyob rau hauv nws qhov kev tshawb nrhiav, nws muab qhov pib zoo rau kev tshawb fawb yav tom ntej kom nkag siab txog qhov cuam tshuam ntawm PD pathology ntawm tib neeg kev paub. Nws kuj tseem qhia tau hais tias peb yuav tsum nyob twj ywm zoo thiab txawm tias PD tuaj yeem cuam tshuam rau peb lub neej, peb yuav tsum tsis txhob tso peb lub cim xeeb lossis lwm yam 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 tseem tuaj yeem tswj hwm qhov sib npaug ntawm cov neurotransmitters, xws li nce qib ntawm acetylcholine thiab kev loj hlob. Cov khoom no tseem ceeb heev rau kev nco thiab kev kawm. Tsis tas li ntawd, Cistanche deserticola kuj tseem tuaj yeem txhim kho cov ntshav khiav thiab txhawb nqa cov pa oxygen, uas tuaj yeem ua kom lub hlwb tau txais cov as-ham txaus thiab lub zog, yog li txhim kho lub hlwb tseem ceeb thiab kev ua siab ntev.

Nyem paub txoj hauv kev los txhim kho koj lub cim xeeb

Muaj cov pov thawj muaj zog hauv vitro uas ua rau mob ua paug, caspase-1-induced -synucleinopathyis cytotoxic (Wang li al., 2016; Ma et al., 2018). Caspase-1 kuj tau pom tias truncate -synuclein ntawm C-terminalend hauv proteolipid protein -synuclein (PLP-SYN) transgenicmouse qauv ntawm MSA, uas txhawb nqa -synuclein aggregation, lub cev muaj zog, thiab txo qis hauv tyrosine hydroxylase. -positiveneurons hauv substantia nigra (Bassil li al., 2016).

Tsis tas li ntawd, tus caspase -1 inhibitor VX-765 yog neuroprotective hauv PLPSYN nas qauv (Bassil li al., 2016). Caspase-zoo li truncation ntawm C-terminal kawg ntawm -synuclein tau tshawb pom thiab pom nyob rau hauv lwm yam PD qauv ntawm transgenic nas, cell culture, thiab recombinant adeno-associated virus injectedrats (Li et al., 2005; Liu et al., 2005; Ulusoy et al., 2010).

Truncated -synuclein nrog rau tag nrho-ntev -synuclein tau pom dav dav hauv lub hlwb tom qab tuag los ntawm cov neeg mob PD thiab cov neeg mob Dementia nrog Lewy lub cev (Suzuki li al.,2018).

Yog li ntawd, thaum microglia thiab astrocytes raug cuam tshuam txog kev mob oxidative kev nyuaj siab, lawv tau nce mus rau kev tso tawm cov pro-inflammatory SASP thiab hloov WT -synuclein rau hauv aPD-hais txog hom tshuaj lom.Senescent neuroglia prime neurons rau neurodegeneration thiab pab txhawb rau cov kab mob ntxov. Piv txwv li, thaum noj qab haus huv neurons yog co-cultured nrog senescent neuroglia, lawv muaj kev txo qis hauv kev ua haujlwm, synapse maturation, synaptic plasticity, synaptic vesicle loj, thiab cuam tshuam neuronalhomeostasis (Bussian li al., 2018; Han li al., 2020 thiab; al., 2020; Sheeler et al., 2020).

Cov xwm txheej cuam tshuam nrog senescentneuroglial-mediated neuronal detriment muaj xws li proinflammatory secretion, txo cov neurotrophic factor secretion, txo glutathione secretion, thiab txo lub peev xwm kom clearextracellular -synuclein (Rodriguez li al., 2015; Burtscher andMillet, 2021).

Tsis tas li ntawd, nws tau pom tias tshem tawm cov teeb meem neuroglia los ntawm cov qauv ntawm neurodegeneration mitigatesreactive gliosis thiab neuronal tuag thaum khaws cia cov kab mob hauv lub cev (Chinta li al., 2018; Salas li al., 2020).

Lub degeneration ntawm dopaminergic neurons nyob rau hauv PD tuaj yeem pib nws tus kheej-propagating voj voog ntawm oxidative kev nyuaj siab, neuroinflammation, neuroglial senescence, neuroglial activation, thiab neuronal tuag.Cov raug mob, degenerative dopaminergic neurons nyob rau hauv PD tso tawm insoluble -synuclein fibrils, ATP, MMP{{2} , thiab neuromelaninin mus rau qhov chaw extracellular (Nws li al., 2021).

Txhawm rau tswj hwm lub hlwb homeostasis, microglia, thiab astrocytes raug ceeb toom kom nqa cov cellular khib nyiab los ntawm degeneratingneurons thiab pib cov lus teb tom qab inflammatory thiab oxidativestress.

Txawm hais tias cov kev ua ntawm neuroglia yog qhov tsim nyog thiab muaj txiaj ntsig zoo hauv lub xeev tsis muaj kab mob, thaum lawv tsis tuaj yeem tiv thaiv cov dej ntws ntawm degeneration, lub voj voog ua rau nws tus kheej-ua kom nrov thiab puas.

Cov teebmeem ntawm Neuroglial Uptake ntawm -Synuclein thiab Ua kom los ntawm -Synuclein

Neurons secrete -synuclein rau hauv qhov chaw extracellular los ntawm exosomal thiab calcium-dependent yam (Emmanouilidouet al., 2010). Tus nqi ntawm -synuclein secretion los ntawm neuronsand neuroblastomas rau hauv qhov chaw extracellular, nrog rau cov concentration ntawm secreted insoluble -synuclein aggregates, nce nyob rau hauv cellular stress-induced protein misfolding thiab puas (Jang li al., 2010).

Kev puas tsuaj, aberrant synuclein yog secreted rau hauv lub extracellular qhov chaw nyob rau hauv stressthrough exocytosis es tsis nyob rau hauv exosomes (Jang li al., 2010).Extracellular qus-hom thiab mutant -synuclein yuav coj upby neurons los yog glia ntawm endocytosis thiab kis ntawm gliaand neurons, txawm nyob rau hauv daim ntawv sib sau ua ke, ua rau muaj kev sib kis ntawm Lewy lub cev (Lee li al., 2011, 2014).

Extracellular non-mutated -synuclein oligomers elicit aninflammation teb los ntawm microglia ntawm paracrine activation ntawm tus xov tooj zoo li receptor 2 (TLR2) (Kim li al., 2013; Lee li al., 2014). Ntxiv mus, extracellular -synuclein tuaj yeem ua raws li kev puas tsuaj ntawm cov qauv molecular (DAMPs) los qhib lwm cov microglial receptors thiab intracellular txoj hauv kev, xws li Fc gamma receptor IIB (Fc RIIB) thiab NF-κB txoj hauv kev (Kam li al., 2020).

Kev ua kom cov receptors thiab txoj hauv kev no ua rau txo qis microglial phagocytosis, cov lus teb upregulatedinflammation, -synuclein nitration, thiab nce ROS (Zhang li al., 2007; Kam et al., 2020; Mavroeidi thiab Xilouri, 2021).

Kev sib cav sib ceg muaj zog txog seb puas tau txais cov microglia muaj teeb meem lossis muaj txiaj ntsig zoo rov qab ntau dua 20 xyoo (Streitet al., 1999). Hauv PD, kev ua haujlwm ntev ntev ntawm microglia nce siab rau neurodegeneration.

Permanentlysenescent microglia txawv los ntawm transiently activatedmicroglia. Microglia ua haujlwm tsis tu ncua hauv kev teb rau lub hlwb raug mob thiab txhawb nqa ob qho tib si pro-inflammatory thiab anti-inflammatory genes ib txhij (Osman li al., 2020).

Txawm li cas los xij, cov kab mob ua kom tsis muaj zog microglia uas feem ntau pom nyob rau hauv neurodegeneration zoo li txawv ntawm senescent microglia hauv semantics nkaus xwb (Lull and Block, 2010; Woodburn li al., 2021). Lawm, muaj qhov sib txawv me ntsis ntawm senescent thiab chronic activated microglia, tab sis lawv zoo li ua haujlwm zoo sib xws hauv PD.

Peb xav tias qhov kev xav tsis zoo, ua haujlwm tsis ntev, lossis ua haujlwm tsis ntev los no qhia txog kev sib txawv ntawm cov neeg nyob hauv microglial thiab cov teebmeem ntawm tus kheej microglial microenvironments (Masuda li al., 2020; Tan et al., 2020). Ua haujlwm raws li qhov kev xav no, qee qhov senescent microglia tuaj yeem txais yuav ua rau lub sijhawm ua haujlwm tsis zoo vim yog lub sijhawm ntxov neurodegenerative milieu thiab pab txhawb rau kev txhim kho ntxiv ntawm neurodegenerationin ib qho mob ntev (Masuda li al., 2020).

Lub sijhawm ua haujlwm microglia pab txhawb rau kev txhim kho ntxov ntawm PD hauv cov lus teb rau kev cuam tshuam nrog -synucleinand nyob twj ywm qhib kom ntev li ntev tau -synuclein tam sim no.Piv txwv li, tus qauv hauv vivo nas uas overexpressed tag nrho-ntev, qus-hom, tib neeg -synuclein nyob rau hauv lub murine Koj-1promoter tau ntsib kev ua kom microglia mus ib txhis (Chesseletet al., 2012).

Activated microglia thawj zaug tshwm sim hauv striata thaum muaj hnub nyoog 1 hli thiab hauv SNpc thaum muaj hnub nyoog li 5 lub hlis, ua ntej kev puas tsuaj ntawm neuronal (Chesselet li al., 2012). Cov neeg uas muaj idiopathic ceev-qhov muag-tsim pw tsaug zog cwj pwm (IRBD) ua haujlwm rau cov pej xeem txaus siab rau kev kawm txog cov cim qhia ua ntej ntawm PD. Cuaj tawm ntawm kaum tus neeg nrog IRBD tau txais kev kuaj mob PD hauv 14 xyoo tom qab tau txais kev kuaj mob IRBD (Iranzo li al.,2016).

Lub pathology yog strikingly zoo sib xws ntawm ob kab mob. Piv txwv li, striatal 18F-DOPA raug txo nyob rau hauv 90% ntawm cov neeg mob IRBD, ua ke nrog unilateral microglia activation hauv SNpc, zoo ib yam nrog PD thaum ntxov (Ouchi, 2017).

Cov kev soj ntsuam no cuam tshuam nrog qhov kev xav tias qhov mob tshwm sim los ntawm chronicallyactivated microglia pab txhawb kev hloov pauv ntawm IRBP mus rau PD ua haujlwm dhau sijhawm. Tseeb, postmortem PD lub hlwb muaj ntau ntau ntawm pro-inflammatory microglia thiab astrocytes nyob rau tib qhov chaw cuam tshuam los ntawm -synucleinopathy (Freund et al., 2012; Chinta et al., 2018; Brás et al., 2020; Harms et al., 2020; Harms et al., 2020. .

Extracellular -synuclein endocytosed los ntawm astrocytes ua rau muaj kev tso tawm ntawm proinflammatory thiab neuroinhibitory secretions, xws li GFAP, cytokines, chemokines, thiab chondroitinsulfate proteoglycan (Vieira li al., 2020). Txawm li cas los xij, muaj qee cov pov thawj tias -synuclein uptake los ntawm astrocytesfollows -synuclein khi rau astrocyte receptors los txhawb cov qog nqaij hlav proinflammatory (Vieira li al., 2020).

Endocytosed synuclein hauv astrocytes ua rau cuam tshuam Ca2+ thiab mitochondrialhomeostasis, oxidative stress, thiab nce qib ntawm glutathioneperoxidase (Mavroeidi thiab Xilouri, 2021). Astrocytes tuaj yeem harborinsoluble -synuclein aggregates (Lee li al., 2010).

Lub uptakeof -synuclein aggregates los ntawm astrocytes yog thawj zaug kev tiv thaiv txheej txheem uas lub hom phiaj kom tshem tawm cov tshuaj lom protein (Booth li al.,2017). Txawm li cas los xij, cov kab mob suav nrog tuaj yeem ua rau lysosomaldysfunction, tuaj yeem nyob hauv astrocytes, thiab yog li ntawd, khaws thiab ua rau cellular puas (Booth et al., 2017). Astrocytes muaj qhov tshwj xeeb susceptibility los ua senescentin teb rau cellular stress.

Nyob rau hauv teb rau oxidative kev nyuaj siab, astrocytes ua senescent ua ntej fibroblasts, neurons, thiab tejzaum nws microglia (Bitto li al., 2010; Chinta li al., 2018). Inpostmortem PD SNpc cov ntaub so ntswg, tib lub xovtooj saib xyuas kom muaj qhov txo qis hauv cov ntaub so ntswg nuclear B1 piv rau controlSNpc cov ntaub so ntswg yog astrocytes (Chinta li al., 2018). Reducedlamin B1 qib yog ib tug ntev-sawv biomarker ntawm cellularsenescence (Freund li al., 2012).

Txawm li cas los xij, microglia yog thawj kab ntawm kev tiv thaiv hauv kev teb rau kev raug mob thiab oxidative kev nyuaj siab.Lawv nthuav tawm ceev ceev mus rau qhov chaw raug mob kom pib phagocytosis thiab ua kom sai sai. Tsis ntev tom qab ntawd, microglia nrhiav astrocytes los ua haujlwm, tso tawm cov teeb meem cuam tshuam, thiab txhawb nqa glutamate-induced excitotoxicity (Liddelow li al., 2017; Iovino li al., 2020; Liu et al., 2020; Matejuk thiab Ransoho, thiab lwm yam).

Yog tias tus qauv no tau pom nyob rau hauv cov kab mob neurodegeneration-koom nrog mob neuroglialactivation, ces microglia yuav dhau los ua "senescent" ua ntej. Txawm hais tias astrocytes ua senescent ua ntej lawv cov neeg nyob ze ntawm tes ua, cov txiaj ntsig ntawm tus neeg sawv cev ua kom muaj kev sib kis ntawm senescence mus rau lwm hom cell (Nelson li al., 2012).

Cov teebmeem ntawm Neuroglial Exposure rau Preformed -Synuclein Fibrils

Muaj peb hom morphological ntawm -synuclein. Los ntawm qhov tsawg tshaj plaws mus rau qhov loj tshaj plaws, lawv yog monomers, oligomers, thiab fibrils.Cov kab mob tseem ceeb ntawm Lewy Lub Cev yog synuclein fibrils. Artificially synthesized "preformed -synucleinfibrils" (PFFs) tuaj yeem raug txhaj rau hauv cov qauv tsiaj ntawm PD los kawm cov spatiotemporal dynamics ntawm -synuclein txav, mob, oxidative kev nyuaj siab, thiab neurodegeneration.

Kev teb rau qhov muaj -synuclein fibrils, neuroglia generatesuperoxide (O2-), ROS, thiab cytotoxic yam (He et al., 2021).PFFs kuj ua rau cov lus teb muaj zog hauv dopaminergic neurons.

Piv txwv li, dopaminergic neurons uas tau kho nrog synthesizedPFFs muaj kev nce qib ntawm serine 129 phosphorylated -synuclein, nce -synuclein aggregation, txo qib ntawm presynaptic protein, axonal thauj protein cuam tshuam, thiab txo dopaminergic ciaj sia taus (Tapias et 17). vim yog PFF-induced mitochondrialdysfunction, nce O2- ntau lawm, nce nitric oxide (NO) ntau lawm, qib protein nitration, thiab o (Tapias li al., 2017).

Hauv kev tshawb fawb tsis ntev los no, PFFs tau txhaj rau hauv striata ntawm kev noj qab haus huv, cov neeg laus, cov tsiaj qus (C57BL / 6) txiv neej nas, uas pib ua rau muaj kev mob tshwm sim hauv ob qho tib si astrocytes thiab microglia (Lai li al., 2021). Lub xeev inflammatory peakedat 7 hnub tom qab txhaj tshuaj (dpi). Aggregates ntawm -synuclein ces nce nyob rau hauv concentration thiab propagation tom qab kaum plaub dpiand peaked ntawm peb caug thiab cuaj caum dpi (Lai li al., 2021).

Thaum kawg, striatal dopaminergic neuron poob thiab lub cev muaj zog tsis ua haujlwm tau pom (Lai li al., 2021). Cov txiaj ntsig zoo sib xws tau pom nyob rau hauv txiv neejFischer 344 nas uas tau txais unilateral intrastriatal txhaj ntawm PFFs (Duffy li al., 2018).

Kev ua kom Microglial thiab kev mob tshwm sim yog thawj cov lus teb rau PFF txhaj tshuaj hauv cov kws kho mob (Duffy li al., 2018). Kev ua kom Microglial nyob rau hauv cov lus teb rau PFF tau kav ntev li ntawm 3 lub hlis ua ntej SNpc neuronaldegeneration tshwm sim thiab pheej mus thoob plaws hauv cov txheej txheem degenerative, qhia tias microglia tau ua haujlwm ntev (Duffy li al., 2018).

Hauv lwm txoj kev tshawb fawb tsis ntev los no tau piav qhia ntawm no, PFF tau ua rau muaj kev cuam tshuam neuroglia, senescent neuroglia, thiab neuronal tuag (Verma li al., 2021). MPP + lossis PFF kev kho mob ntawm cultureddopaminergic nas N27 hlwb ua rau cov hlwb qhia cov cim cim, xws li txo qis ntawm Lamin B1 thiab HMGB1 thiab nce qib ntawm p16 thiab p21.

PFF kev kho mob ntawm culturedprimary astrocytes thiab microglia los ntawm C57BL / 6 tsiaj qus miceal kuj ua rau senescence, raws li pov thawj los ntawm kev txo qis Lamnin B1, HMGB1, AT-nplua nuj sequence-binding protein 1 (SATB1), thiab p16levels, tab sis siab p21. Interestingly, muaj ib txhij tsim ntawm senescent thiab reactive astroglia nyob rau hauv teb cov kab lis kev cai PFF kev kho mob.

Qhov kev soj ntsuam no yuav cuam tshuam qhov sib txawv subpopulations ntawm astrocytes (Miller, 2018). Micethat tau txais kev txhaj tshuaj PFF lub hlwb los ntawm cov cannula qhia txog qhov kev hloov pauv ntawm cov cim senescent. Piv txwv li, ventralmidbrain thiab SNpc ntawm cov nas no tau ntsib kev txo qis ntawm Lamnin B1, HMGB1, thiab p16 qib thiab nce qib ntawm p21.Kev nce qib ntawm GFAP thiab Iba-1 kuj tau pom, qhia txog cov reactive astroglia thiab microglia feem. Ntxiv mus, muaj pov thawj ntawm kev tuag neuronal los ntawm kev txo qis ntawm -IIItubulin.

Thaum kawg, SNpc cov ntaub so ntswg los ntawm postmortem PD cov neeg mob tau lees paub qhov kev koom tes ntawm cellular senescence los ntawm westernblot tsom xam. Lamnin B1, HMGB1, thiab SATB1 tau txo qis, p21 qib tau nce thiab p16 qib tseem tsis hloov pauv hauv lub hlwb postmortem PD piv rau kev tswj cov ntaub so ntswg midbrain.Qhov kev sim tau los ntawm Verma li al. (2021) qhia tau hais tias ua li cas pathologic -synuclein instigates ib txhij neuroglialsenescence thiab neuroglial activation uas nws thiaj li ua rau PD-txog neuronal tuag.

SENOLYTICS AS A THERAPEUTICAVENUE FOR PARKINSON'S DISEASE

Senescent hlwb ua rau muaj ntau yam kab mob uas muaj hnub nyoog.Txawm li cas los xij, lawv cov kev tshem tawm txo qis lawv cov kab mob cuam tshuam thiab ua rau muaj kev noj qab haus huv ntxiv. Kev txo qis ntawm SATB1 protein nyob rau hauv dopaminergic neurons tsis ntev los no tau pom tias yog ib qho kev pheej hmoo rau PD (Brichta li al., 2015; Changet al., 2017; Nalls li al., 2019; Riessland, 2020).

Tsis tas li ntawd, noob caj noob ces knockout ntawm Satb1 ua rau cellular senescence thiab nthuav qhia ntawm p21 thiab CDKN1A nyob rau hauv tib neeg embryonicstem hlwb uas tau sib txawv rau hauv dopaminergic neurons (Riessland li al., 2019). Riessland et al. (2019) kuj tau qhia qhov tshwm sim no nyob rau hauv nruab nrab ntawm cov nas los ntawm kev siv astereotactic adeno-associated virus 1 txhaj tshuaj qhia shRNA(AAV1-shRNA) kom downregulate Satb1, uas tom qab nce p21 qhia thiab neuronal senescence.

Thaum kawg, kev kho mob nrog AAV1-shRNA tshem tawm tyrosine hydroxylase-expressing neurons, txo tus naj npawb ntawm mitochondria, upregulated Cdkn1a, thiab ua rau lub cev tsis muaj zog (Riessland li al., 2019). Tsis tas li ntawd, postmortem SNpc cov ntaub so ntswg los ntawm cov neeg mob PD tau nce p21 qhia thiab txo qis kev ua haujlwm ntawm SATB1 (Brichta li al., 2015; Riessland li al., 2019; Riessland, 2020). Inhibition ntawm p21 hauv SATB1 knockouthuman dopaminergic neurons los ntawm p21 inhibitor UC2288 ua rau txo qis cov teebmeem ntawm senescence yam tsis tau tsim kev loj hlob (Riessland li al., 2019).

Tsis tas li ntawd, kev kho mob ntawm SATB1 knockout tib neeg dopaminergic neurons nrog CDKN1Ashort hairpin RNA (shRNA) txo qis p21 qib thiab lwm cov cim tseem ceeb (Riessland li al., 2019). Tsis tas li ntawd, UC2288 tsis ntev los no tau pom tias txo qis cov cim cim xws li oxidative kev nyuaj siab thiab mob hauv MPTP mousemodel ntawm PD (Im li al., 2020). Yog li, UC2288 tej zaum yuav yog aviable anti-senescent tus neeg saib xyuas rau PD.

Astragaloside IV (AS-IV) yog ib qho tshuaj tua kab mob uas tau muab los ntawm cov nroj tsuag tshuaj ntsuab Astragalus membranaceus. ASIV muaj keeb kwm ntev hauv Suav tshuaj ntsuab vim nws muaj txiaj ntsig zoo, xws li ua lub zog antioxidant, antifibrotic, thiab cov tshuaj tiv thaiv kab mob (Li et al., 2017). AS-IVis neuroprotective hauv thawj dopaminergic nigral cell kab lis kev cai nthuav tawm rau 6-hydroxydopamine (Chan et al., 2009).

Cov nas kho mob nrog MPTP thiab cov tshuaj probenecid muaj kev poob qis ntawm dopaminergic neurons hauv SNpc thiab raug kev txom nyem los ntawm cov leeg nqaij thiab kev sib npaug (Xia li al., 2020).Txawm li cas los xij, thaum tau txais kev kho mob nrog AS-IV, dopaminergicneurons thiab lub cev muaj zog tsis txaus hauv MPTP thiab probenecid-kho miceh muaj kev tiv thaiv tseem ceeb yam tsis hloov MPTP metabolism (Xia li al., 2020).

Ib qho kev tshawb nrhiav tseem ceeb los ntawm Xia thiab al.(2020) txoj kev tshawb fawb yog tias AS-IV kev kho mob txo SNpcconcentration ntawm senescent astrocytes hauv MPTP nas qauv thiab txhim kho ntau cov cim ntawm cellular senescence, xws li nce qib p16 thiab txo qis ntawm lamin B1 hauv cellular nucleus. . Tsis tas li ntawd, tej yam ntuj tso lub hnub nyoog muaj feem xyuam rau senescence thiab ntxov ntxov senescence vim MPP + kev kho mob nyob rau hauv cov kab lis kev cai primaryastrocyte los ntawm nas tau pom tias yuav inhibited los ntawm kev kho mob AS-IV (Xia li al., 2020).

AS-IV tau pom tias muaj cov nyhuv anti-senescent los ntawm kev txhawb nqa mitophagy thiab nws cov khoom tiv thaiv oxidant (Xia li al., 2020).Nws tsis ntev los no tau pom tias astrocyte thiab microgliasenescence hauv PD tuaj yeem txo tau los ntawm kev kho mob senolytic nrog cov ntshav thiab glucocorticoid-txog kinase. 1 (SGK1)inhibitor GSK-650394 (Kwon et al., 2021). NF-kB transcriptionfactors yog lub luag hauj lwm rau transcribing pro-inflammatory genes, nrog rau cov cytokines thiab chemokines (Liu li al., 2017).

Los ntawm phosphorylation, SGK1 qhib txoj hauv kev NF-kB thiab txhawb cov lus teb inflammatory (Lang and Voelkl, 2013). GSK650394 txo cov qib cytokine thiab SGK1 overexpression boostedcytokine theem nyob rau hauv kab lis kev cai nas astrocytes thiab microglia los ntawm lub cortex thiab ventral midbrain (Kwon li al., 2021). Tsis tas li ntawd, Nurr1 thiab Foxa2 downregulate Sgk1 nyob rau hauv nas-cultured glia, raws li qhia nyob rau hauv microarray thiab RNA-seq cov ntaub ntawv (Kwon et al., 2021). Xya tawm ntawm kaum saum toj kawg nkaus genes uas tau downregulated los ntawm GSK-650394 muaj kev tiv thaiv kab mob. -txog ontologies (Kwon et al., 2021).

Yog li ntawd, cov tshuaj tiv thaiv kab mob ntawm Nurr1 thiab Foxa2 inglia yog vim inhibitory kev ua ntawm Sgk1.Nws kuj tau pom tias SGK1 inhibition suppressesinflammation txoj kev cuam tshuam nrog NLRP3inflammasome thiab CGAS-STING, upregulates glutamateclearance los ntawm glia thiab tiv thaiv glial mitochondrial puas (K et al., 2021).

Thaum kawg, SGK1 inhibition txo qis cov cim glialsenescent xws li SA- -gal, txo qis cov noob caj noob ces nrog SASP, txo qis cov protein ntau, txo qis cov pa oxygen ntau lawm, thiab txo qis cov noob caj noob ces (Kwon li al., 2021). Qhov tseem ceeb, mousemidbrain dopaminergic neurons uas overexpressed tib neeg -synuclein tau co-cultured nrog nas ventral midbrainastrocytes thiab microglia.

Cov kab lis kev cai no tau kho nrog PFFs.Culture kho nrog GSK-650394 los yog SGK1 knockdown nyob rau hauv glia txo -synuclein pathology nyob rau hauv neurons xws li -synuclein neuron-rau-neuron hloov, muab lawv co-cultured nrog ventral midbrain glia (Kwon et al., 2021). Tsis tas li ntawd, SGK1 inhibition nyob rau hauv nas ventral midbrainastrocytes thiab microglia co-cultured nrog nas midbraindopaminergic neurons tiv thaiv cov neurons los ntawm toxicinsults los ntawm H2O2.

Thaum kawg, SGK1 genetic silencing lossis GSK650394-kev cuam tshuam cuam tshuam hauv MPTP nas qauv ntawm PD tiv thaiv kev coj cwj pwm tsis zoo, midbrain dopaminergicneuron poob, thiab suppressed SNpc o thiab senescence (Kwon li al., 2021).B-cell lymphoma-extra loj (Bcl-xL) yog ib tug tswv cuab ntawm Bcl-2protein tsev neeg thiab nyob hauv mitochondrial membranes. Bcl-xLhas anti-apoptotic zog kho los ntawm nws inhibition ntawm mitochondrial cytochrome c tso tawm (D'Aguanno thiab Del Bufalo, 2020).

Tsis tas li ntawd, Bcl-xL kuj muaj cov khoom muaj txiaj ntsig zoo.Piv txwv li, nws yog qhov xav tias cov hlwb puas uas tsis yog los rau apoptosis tuaj yeem hloov pauv los ntawm kev tshaj tawm ntawm Bcl-xL (Mas-Bargues li al., 2021). Bcl-xL kuj tseem txhawb nqa cov metabolism hauv mitochondrial thiab ua kom cov txiaj ntsig ntawm ATP synthesis, ob qho tib si yog qhov tsim nyog los txhawb kev tsim cov SASP ntawm cov hlwb senescent (Herranz thiab Gil, 2018; Mas-Bargues li al., 2021).

Hauv kev kuaj ntshav tom qab lub hlwb los ntawm cov neeg mob PD, nws tau pom tias Bcl-xL qhia hauv mesencephalon dopaminergicneurons nyob ze rau ob zaug siab li hauv kev tswj hwm (Hartmannet al., 2002). Interestingly, Bcl-xL yuav muaj feem cuam tshuam nrog sporadicPD los ntawm pro-senescence thiab kev tiv thaiv Parkin. Cov xwm txheej tsis zoo, PINK1 protein koom tes nrog cov protein Parkin hloov mus rau polarized mitochondria thiab ua rau mitophagy. Txawm li cas los xij, hloov pauv E3 ubiquitin ligase Parkinand pathological mitochondrial bioenergetics yog cuam tshuam inautosomal recessive tsev neeg PD (Dawson thiab Dawson, 2010).Nws tau pom tias Bcl-xL antagonizes lub peev xwm ntawm PINK1and Parkin los txhawb mitophagy (Maset202. ).

Disrupted midbrain mitophagy yog lub hauv paus pathological muaj nyob rau hauv ob qho tib si PD cov neeg mob thiab PD tsiaj qauv (Liuet al., 2019). Yog li ntawd, nws zoo nkaus li tias Bcl-xL inhibitors, xws li A1331852 thiab A1155463, tuaj yeem ua tau zoo cov tshuaj tua kab mob PD los ntawm kev txhawb nqa mitophagy (Zhu li al., 2017).Kev sib raug zoo ntawm PD pathology thiab Bcl-xL iscomplicated. Zoo li cellular senescence, Bcl-xL zoo li muaj lub peev xwm hauv PD rau kev tiv thaiv neuroprotection, nrog rau kev ua rau mob hnyav dua.

Piv txwv li, SH-SY5Y hlwb hloov nrog adopamine transporter tiv taus MPP + thaum kho nrog Bcl-xL (Dietz li al., 2008). SH-SY5Y hlwb overexpressing Bcl-xLwere kuj resistant rau 6-hydroxydopamine-induced tuag (Jordánet al., 2004). Tsis tas li ntawd, SH-SY5Y hlwb overexpressing Bcl-xLpreserved mitochondrial dynamics los ntawm anti-oxidative stressmechanisms thaum LRRK2 yog pharmacologically inhibited los ntawm GSK2578215A (Saez-Atienzar li al., 2016). Tsis tas li ntawd, Bcl-xLtreatment tau pom tias yog neuroprotective hauv MPTP mousemodel ntawm PD (Dietz li al., 2008).

Thaum kawg, Bcl-xL yog qhov tsim nyog rau CNS synapse tsim, synaptic vesicle membrane dynamics, thiab neurite outgrowth, tag nrho cov uas ua cuam tshuam thaum lub sij hawm neurodegeneration (Li li al., 2008, 2013; Park et al., 2015). Hauv kab lis kev cai ntawm tes thiab cov qauv nas tsis zoo ntawm PD, lawv tau tsa qee qhov kev tsis txaus siab rau kev ua raws li cov kab mob senolytic Bcl-xL antagonists raws li txoj kev kho mob.

Txawm hais tias muaj peev xwm ua tau ob lub luag haujlwm ntawm Bcl-xL hauv PD, tej zaum qhov sib txawv tuaj yeem raug txheeb xyuas thiab ua rau muaj txiaj ntsig. Cov Bcl-xL cov protein tuaj yeem raug tshem tawm ntawm nws cov N-terminus los ntawm caspase-dependent mechanisms los tsim 1N-Bcl-xL fragments.Bcl-xL fragmentation yog nce thaum glutamate-inducedneuroexitotoxicity, uas feem ntau tshwm sim hauv ntau cov kab mob neurodegenerative, suav nrog PD (Park thiab Jonas. , 2017; Iovino et al., 2020).

Kev sib sau ntawm 1N-Bcl-xL fragmentsinduces mitochondrial raug mob, xws li elevated membraneconductance thiab nce cytochrome c tso, nws thiaj li ua rau neuronal tuag (Park thiab Jonas, 2017). Lub senolyticABT-737 khi rau ob qho tib si Bcl-xL thiab 1N-Bcl-xL, tiv thaiv 1N-Bcl-xL los ntawm kev puas tsuaj mitochondria, thiab tiv thaiv Bcl-xL los ntawm kev tsim 1N-Bcl-xL tawg (Park thiab Jonas, 2017).

Tsis tas li ntawd, nws tau raug pom tias cov teebmeem ntawm Bcl-xL senolytics yog qhov concentration-dependent. Piv txwv li, siab concentrations ntawm ABT-737 (1 µM) thiab WEHI-539(5 µM) exacerbated neurotoxicity los ntawm glutamate, cuam tshuam mitochondria membrane muaj peev xwm, thiab txo cov cellularconcentration ntawm ATP (Park li al., 2017) . Conversely, lowconcentration ntawm ABT-737 (10 ηM) thiab WEHI-539 (10 ηM) yog neuroprotective tiv thaiv glutamate-induced cell tuag los ntawm kev tiv thaiv mitochondrial membrane muaj peev xwm thiab khaws cia ATP poob (Park et al., 2017).

Ua ke, cov pov thawj zoo li hais tias Bcl-xL tseem tuav cov lus cog tseg raws li lub hom phiaj hauv kev kho mob los tiv thaiv kev laus ntawm PD, tab sis qhov concentration ntawm Bcl-xL tshwj xeeb senolytics thiab Bcl-xL fragmentationpotential yuav tsum tau muab coj los xav. Txij li thaum Bcl-xLfragmentation tshwm sim hauv cov lus teb rau glutamate neurotoxicity, tej zaum Bcl-xL-specific senolytics yuav muaj txiaj ntsig ntau dua ua ntej tus kab mob pib.Anti-senescent lossis senescent cell tshem tawm cov tswv yim zoo li muaj txoj hauv kev tshiab ntawm kev kho tshuaj rau cov neeg mob PD.Txawm li cas los xij, feem ntau ntawm Cov pov thawj tam sim no raug txwv andrestricted rau cell thiab tsiaj qauv raws li tau piav nyob rau hauv Table 1.Qhov tseeb, feem ntau ntawm cov kev tshawb fawb kho mob ntawm senolytics yog preclinical (Romashkan li al., 2021).

Txawm li cas los xij, thawj qhov qhib-daim ntawv sau npe, ib leeg-caj npab kev soj ntsuam ntawm senolytics hauv tib neeg cov neeg mob tau tshaj tawm xyoo 2019 (Kev Ncaj Ncees li al., 2019; Nkauj li al., 2020). Qhov kev tshawb fawb no tau pom tias lub sijhawm luv luv (3 lub lis piam) kev kho mob senolyticcells hauv cov neeg mob uas muaj idiopathic pulmonary fibrosis nrog dasatiniband quercetin (D + Q) txhim kho cov tsos mob thiab kev ua haujlwm (Justiceet al., 2019; Song et al., 2020). Txij thaum ntawd los, D + Q kuj tau pom tias muaj txiaj ntsig zoo ntawm kev txo qis cov hlwb hauv cov neeg mob ntshav qab zib mellitus (Hickson li al., 2019).

Tau muaj kev nce zuj zus ntawm tus lej thiab thaj tsam ntawm kev sim tshuaj kho mob nyob rau hauv kev tshawb fawb hauv lub xyoo dhau los no (Kirkland thiab Tchkonia, 2020; Song li al., 2020; Wissler Gerdeset al., 2020). Tib lub sijhawm, kuj tseem muaj cov tuam txhab tshuaj kho mob sai sai thiab kev nqis peev nyiaj txiag tshwj xeeb tshwj xeeb rau kev txhim kho senolytics nyob rau xyoo tas los no (Dolgin, 2020). Muaj kaum plaub qhov kev tshawb fawb soj ntsuam tam sim no teev nyob rau ntawm ClinicalTrials.gov uas tshwm sim los ntawm kev tshawb nrhiav "senolytic" hauv "lwm yam. "search field.

Plaub qhov kev sim no tsom rau kev mob osteoarthritis, plaub yog tsom rau txo qis COVID-19, thiab qhov seem ntawm qhov cuam tshuam ntawm femoroacetabular impingement, tsis muaj zog ntawm cov neeg laus muaj sia nyob ntawm kev mob qog noj ntshav thaum yau, mob raum, thiab kev txhim kho pob txha ntawm cov neeg laus noj qab haus huv. Hauv ntau hom kev sib xyaw ua ke thiab kev siv tshuaj, senolytics D, Q, thiab fisetinare suav nrog kev cuam tshuam tshuaj hauv txhua qhov kev kuaj mob no. Ib qho ntawm cov kev sim osteoarthritis suav nrog fisetin thiab cov tshuaj tiv thaiv kab mob losartan.

Lwm qhov kev sim osteoarthritis tam sim no suav nrog Q, fisetin, thiab glycyrrhizin asinterventions. Glycyrrhizin muaj anti-inflammatory thiab antiviralproperties. Yav dhau los los yog npaj senolytic-tsom mus soj ntsuam trialshave ua hauj lwm rau lawv siv nyob rau hauv kev kho mob ntawm hyperoxia-induced reactive pa kab mob, insulin tsis kam, ntshav qab zib, preeclampsia, fatty siab kab mob, rog rog, macular degeneration, thiab mob raum mob raum (Kirkland thiab Tchkonia, 2020; Song. et al., 2020).

Tawm ntawm kaum plaub qhov kev tshwm sim, tsuas yog ob qhov kev sim no tsom mus rau kev ua haujlwm ntawm neurodegeneration: tus tsav thiab theem II sim ntawm SToMPAD txoj kev tshawb fawb (Senolytic Therapy to Modulate the Progressionof Alzheimer's Disease). Txoj kev tshawb nrhiav kev sim (ClinicalTrials.govIdentifier: NCT04063124) tsom rau kev siv D + Q tiv thaiv cov neeg mob Alzheimer's thaum ntxov tshaj 12 lub lis piam (Gonzales li al., 2022).

Txoj Kev Kawm Phase II SToMPAD tam sim no nrhiav neeg ua haujlwm thiab npaj yuav suav nrog ob tus neeg mob nrog Alzheimer's disease thiab Mild Cognitive Impairment (ClinicalTrials.gov Identifier: NCT04685590). Nws yog qhov kev cia siab tias kev kho mob senolytic zoo rau cov neeg mob PD thiab lawv tsev neeg yuav muaj tseeb nyob rau yav tom ntej tsis dhau deb.

TEEB MEEM

Tus kab mob Parkinson yog qhov mob tshwm sim ntau tshaj plaws thiab qhov thib ob feem ntau tshwm sim neurodegenerative disorder.Txawm li cas los xij, cov kab mob nyuaj tseem tsis tau nkag siab tag nrho lossis muaj kev kho mob. Txoj kev tshawb fawb ntawm PD tau tsom mus rau cov neurons ntau vim tias tus kab mob no tau cim los ntawm kev nce qib ntawm cov neurodegeneration. Kev tshawb fawb PD kuj tseem yog qhov tseem ceeb ntawm kev sib koom ua ke -synuclein vim lawv yog cov cim tseem ceeb ntawm tus kab mob. Txawm li cas los xij, neuroglia account rau ib feem loj ntawm lub hlwb thiab yog lub luag haujlwm rau ntau yam haujlwm tseem ceeb hauv CNS.

Lub luag haujlwm ntawm neuroglia hauv cov kab mob neurodegenerative tsis txaus siab. Targeting senescent neuroglia nyob rau hauv PD yog ib qho kev zoo siab tuaj yeem kho txoj kev. Kev sim tshuaj ntawm cov tshuaj tiv thaiv senescent tsis ntev los no tau pib ua tiav thiab tuav cov lus cog tseg ntau.

AUTHOR CONTRIBUTIONS

Txhua tus kws sau ntawv tau pab sau cov ntawv sau, tau tshuaj xyuas cov ntawv sau, thiab pom zoo rau nws daim ntawv tam sim no. RLoversaw lub Scope thiab kev nce qib ntawm cov ntawv sau, sau cov ntawv kawg, thiab ua cov duab kawg.

NYIAJ

Txoj haujlwm no tau txais nyiaj los ntawm Eastern Nazarene CollegeInstructional thiab Professional Development Committee thiab los ntawm Pluripotent Diagnostics.

TXOJ CAI

Peb xav ua tsaug rau txhua tus tswv cuab ntawm PluripotentDiagnostics thiab Biology Department ntawm Eastern NazareneCollege rau lawv cov tswv yim thiab kev sib tham muaj txiaj ntsig. Peb kuj xav ua tsaug rau Pluripotent Diagnostics Scientific AdvisoryBoard rau lawv txoj kev koom tes thiab kev txhawb nqa txuas ntxiv.

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