Neuroglial Senescence, -Synucleinopathy, Thiab Therapeutic Potential Of Senolytics hauv Parkinson's Disease Part 1

Taw qhia

Parkinson's disease (PD) yog cov kab mob neurodegenerative feem ntau uas feem ntau cuam tshuam nrog kev poob ntawm lub cev muaj zog. Nws kuj yog qhov thib ob uas muaj kab mob neurodegenerative tshaj plaws ntxiv rau Alzheimer's disease.

Nyob rau hauv xyoo tas los no, kev tshawb fawb tau qhia txog kev sib raug zoo ntawm kev tawm dag zog thiab kev nco. Raws li kev nrawm ntawm tib neeg lub neej niaj hnub nrawm thiab lawv nyob hauv kev ua haujlwm siab thiab kev kawm ib puag ncig, ntau tus neeg maj mam tsis quav ntsej qhov tseem ceeb ntawm kev ua si. Tsis tas li ntawd, tsis muaj kev ua kis las tsis tsuas yog cuam tshuam rau lub cev kev noj qab haus huv tab sis tseem ua rau mob nco.

Ua ntej, cia peb saib kev sib raug zoo ntawm kev tawm dag zog thiab lub hlwb thiab kev nco txog kev noj qab haus huv. Feem ntau, tib neeg lub hlwb tsim cov neurons, uas yog cov hlwb uas nqa cov teeb liab thoob plaws hauv lub cev. Kev sib txuas ntawm cov neurons ua rau peb lub cim xeeb. Vim tias kev nco tau khaws cia hauv kev sib txuas thiab kev sib txuas lus ntawm ntau cov neurons, lub hlwb yog qhov nyuaj, thiab txhua yam uas cuam tshuam rau cov neurons, suav nrog kev ua neej, noj zaub mov, pw tsaug zog, thiab kev tawm dag zog, muaj peev xwm cuam tshuam rau peb lub hlwb ua haujlwm.

Thib ob, los ntawm kev xav ntawm lub cev, kev tawm dag zog pab tswj kev noj qab haus huv ntawm tib neeg lub cev thiab txhawb cov ntshav ncig. Thaum lub sijhawm ua haujlwm, cov pa oxygen thiab cov as-ham loj thauj mus rau lub hlwb los ntawm cov ntshav, uas muaj txiaj ntsig zoo rau lub hlwb kev noj qab haus huv. Nyob rau tib lub sijhawm, kev tawm dag zog tuaj yeem tso cov endorphins hauv lub cev, uas yog cov tshuaj neurotransmitter uas tuaj yeem txhim kho lub siab thiab txo kev ntxhov siab, uas muaj txiaj ntsig zoo rau kev txhim kho tib neeg kev nco, kev xav, thiab kev muaj tswv yim.

Thaum kawg, txoj kev tshawb fawb loj pom tau tias ntev npaum li koj tawm dag zog tsawg kawg 150 feeb hauv ib lub lis piam, koj tuaj yeem txhim kho kev nco thiab kev kawm tau zoo. Tsis tas li ntawd, ntau yam kev ua si xws li ua luam dej, khiav, nce toj, caij tsheb kauj vab, seev cev, thiab lwm yam tuaj yeem txhawb nqa tib neeg lub hlwb thiab muaj txiaj ntsig zoo rau kev txhim kho kev nco.

Yog li ntawd, peb yuav tsum ntseeg ruaj khov rau txoj kev sib raug zoo ntawm kev tawm dag zog thiab kev nco, ua tib zoo saib xyuas qhov zoo ntawm kev tawm dag zog ntawm lub hlwb, thiab nquag tawm tswv yim thiab xyaum ua lub neej noj qab haus huv kom ua tiav kev noj qab haus huv ntawm lub cev thiab lub hlwb. Nws tuaj yeem pom tias peb yuav tsum txhim kho kev nco, thiab Cistanche deserticola tuaj yeem txhim kho kev nco zoo vim Cistanche deserticola yog cov khoom siv tshuaj hauv Suav teb uas muaj ntau yam teebmeem, ib qho ntawm kev txhim kho kev nco. Kev ua tau zoo ntawm Cistanche deserticola los ntawm ntau yam khoom xyaw uas nws muaj, suav nrog tannic acid, polysaccharides, flavonoid glycosides, thiab lwm yam. Cov khoom xyaw no tuaj yeem txhawb lub hlwb kev noj qab haus huv los ntawm ntau txoj hauv kev.

Nyem paub 10 txoj hauv kev los txhim kho kev nco

Txawm hais tias PD raug suav hais tias feem ntau yog ib qho teeb meem ntawm kev txav mus los, nws tuaj yeem tshwm sim nrog cov tsos mob tsis zoo xws li kev tswj lub zais zis, kev pw tsaug zog, kev ntxhov siab, thiab cem quav.

Qhov kev pheej hmoo rau PD nce nrog lub hnub nyoog, txiv neej poj niam txiv neej, tshuaj tua kab, thiab melanoma (Chen et al., 2017; Delamarre thiab Meissner, 2017; Ye et al., 2020). Hloov pauv, PD muaj feem cuam tshuam nrog kev siv nicotine, caffeine. noj, thiab urate theem (Chen li al., 2013; Bakshi li al., 2015; Delamarre thiab Meissner, 2017; Marras li al., 2019).

Ntau qhov kev hloov pauv tau cuam tshuam nrog kev pheej hmoo siab. Tsev neeg PD txuas nrog cov noob xws li SNCA, PRKN, LRRK2, PINK1, FBX07, PLA2G6, thiab lwm yam (Blauwendraat li al., 2020). Cov mob SporadicPD tau cuam tshuam nrog kev hloov pauv hauv cov noob xws li GBA, ACMSD, STK39, NMD3, STBD1, GPNMB, FGF20, MMP16, STX1B, ITGA8, thiab lwm yam (Chai thiab Lim, 2013).

Lub hauv paus pathophysiology ntawm PD yog txuas rau oxidative kev nyuaj siab thiab mob (Hald and Lotharius, 2005; Chen li al., 2018). Cov kev sib tham tsis ntev los no kuj tau hais txog lub luag haujlwm ntawm lipidopathy hauv PD pathology (Fanning li al., 2020). Txawm li cas los xij, proteinopathy yog lub cim ntawm tus kab mob, vim nws yog nyob rau hauv ntau cov kab mob neurodegenerative.

Lub hom phiaj tseem ceeb ntawm neurodegenerative pathophysiology tau keeb kwm nyob rau hauv lub luag haujlwm ntawm misfoldedpathogenetic proteins. Piv txwv li, amyloid-beta peptides muaj feem cuam tshuam rau Alzheimer's disease, TAR DNA-binding protein 43is cuam tshuam rau hauv amyotrophic lateral sclerosis thiab frontotemporallobar degeneration, cov protein yos hav zoov yog cuam tshuam hauvHuntington's kab mob, thiab -synuclein cuam tshuam hauv PD20, Arrasinate thiab PDkday (Arrasinate). thiab al., 2012; Stefanis, 2012; Blokhuis et al., 2013; Cheignon et al., 2018).

Tsis tas li ntawd, ntau cov kab mob neurodegenerative koom nrog kev sib sau ntawm cov protein ntau, suav nrog Alzheimer's disease, amyotrophic lateralsclerosis, frontotemporal lobar degeneration, thiab PD (Spillantiniand Goedert, 2013; Eftekharzadeh li al., 2018).

Kev laus yog qhov txaus ntshai tshaj plaws rau kev tsim PD (Reeveet al., 2014). Cuaj lub cim tseem ceeb ntawm kev laus ntawm cellular muaj xws li genomic instability, telomere attrition, epigenetic alterations, poob ntawm proteostasis, deregulated nutrient sensing, mitochondrialdysfunction, cellular senescence, qia cell qaug zog, thiab thaum kawg, hloov intercellular kev sib txuas lus, uas yog txuas nrog o. ., 2013).

TheGeroscience Hypothesis txheeb xyuas xya "txoj haujlwm ntawm kev laus" hauv qab no: macromolecular puas, epigenetics, o, hloov mus rau kev ntxhov siab, proteostasis, qia hlwb thiab kev tsim dua tshiab, thiab metabolism (Kennedy li al., 2014).

Cov hlwb senescent tau txuas nrog rau cov txheej txheem kev laus.The senescence-associated secretory phenotype (SASP) ofsenescent cells tso tawm pro-inflammatory cytokinesand, thiab chemokines, thiab txhawb kev mob (Coppé li al., 2008). Tam sim no tsim Unitary Theory of Fundamental AgingMechanisms piav qhia txog cellular facets ntawm aging raws li kev sib cuam tshuam zoo heev uas kho lub hom phiaj ntawm ib sab, xws li cellular senescence, yuav txo tau ntau, los yog tag nrho, ntawm lwm tus (Tchkonia li al., 2021).

Tsis tas li ntawd, Unitary Theory of Fundamental Aging Mechanismsidenifies more other aging-related-related hallmarks xws li cov fibrosis nce, nce CD38, txo NAD +, thiab cov tsub zuj zuj ntawm misfolded thiab aggregated proteins (Tchkonia li al., 2021). AgingMechanisms, kev sib raug zoo ncaj qha yuav tsum muaj nyob ntawm senescentcells thiab proteinopathy.

Txij li thaum feem ntau ntawm cov kev tshawb fawb tau ua onsenescent hlwb tau tsom mus rau peripheral cov ntaub so ntswg, nws yog tshwj xeeb tshaj yog txaus siab los tshawb txog kev sib raug zoo ntawm senescent hlwb thiab proteinopathy nyob rau hauv lub hauv paus paj hlwb (CNS) (Baker and Petersen, 2018). Ntawm no, peb tshawb nrhiav kev sib raug zoo ntawm synucleinopathy, senescent astrocytes, thiab senescent microglia inPD. Tsis tas li ntawd, lub peev xwm ntawm kev tshuaj ntsuam xyuas kev kho mob hauv PD yuav tau tham txog.

-SYNUCLEINOPATHY hauv PARKINSON'SDISEASE

Cov protein -synuclein yog me me (14 kDa), soluble, intrinsically unstructured, thiab encoded los ntawm SNCA noob (Uversky, 2003). Qhov xwm txheej ntawm lub cev tsis zoo ntawm monomeric synuclein yog qhov ruaj khov thiab khaws cia thoob plaws hom tsiaj ntawm tes (Theillet li al., 2016). -synuclein nyob ubiquitously hauv CNSpresynaptic terminals (Jakes li al., 1994).

Txawm hais tias qhov ua haujlwm zoo ntawm -synuclein tsis to taub zoo, nws paub tias yuav koom nrog qee lub luag haujlwm xws li neurotransmitterrelease thiab synaptic plasticity, dopamine metabolism, membraneremodeling, thiab kho DNA (Bendor li al., 2013; McCannet al., 2014; Schaser et al., 2019). Feem ntau -synucleinisoform pom nyob rau hauv tib neeg yog 140 amino acids ntev (Jakes li al.,1994; Goedert li al., 2017).

Nyob rau hauv ib txwm physiological tej yam kev mob, tus qauv ntawm -synuclein resists aggregation. N-terminal thaj tsam isamphipathic, muaj pH yooj yim, khi rau daim nyias nyias, thiab hloov los ntawm cov qauv tsis sib haum mus rau cov qauv -helical thaum ua rau lipids (Bartels li al., 2010, 2011; Theillet li al., 2016). N-terminal cheeb tsam nthuav tawm thawj 60 qhov seem ntawm synuclein thiab yog qhov chaw ntawm peb tsev neeg PD kev hloov pauv: A30P, E46K, thiab A53T (Ono, 2017).

Lub N-terminal regionals kuj suav nrog qhov pib ntawm kev ncab ntawm xya imperfectrepeats ntawm "KTEKEGV" (Dettmer li al., 2015). N-terminalacetylation destabilizes -synuclein, nce -synuclein ntau ntau, thiab txhim kho -synuclein toxicity (Vinueza-Gavilanes li al.,2020). Lub hauv paus core spans los ntawm residues 61 mus rau 95 thiab muaj hydrophobic amino acids.

Lub cheeb tsam hauv nruab nrab kuj tseem hu ua non-amyloid- tivthaiv (NAC) thiab yog qhov chaw tseem ceeb rau kev sib tsoo thiab sib sau ua ke (Ono, 2017). Hauv cov tsiaj qus-synuclein, NAC raug tiv thaiv los ntawm cytoplasmic raug vim muaj kev cuam tshuam ntev ntawm N-terminal thiab C-terminal, uas ua rau tiv thaiv kev sib sau (Bertoncini li al., 2005; Theillet li al., 2016).

Tsis tas li ntawd, cov kws kho mob paub tias khi rau N-terminus aroundtyr39, uas ntxiv pab tiv thaiv kev sib sau ua ke (Burmannet al., 2020). Kev hloov pauv hauv N-terminal tau pom tias cuam tshuam kev sib cuam tshuam ntawm N-terminal thiab C-terminal los txhawb cov pathological nce-ntawm-function synuclein aggregation (Bertoncini li al., 2005).

Qhov seem ntawm qhov tsis zoo "KTEKEGV" rov motifs muaj nyob hauv thaj av NAD. C-terminal yog intrinsically tsis meej pem thiab yog acidic heev (Suzuki li al., 2018). Cov qauv ntawm -synucleinis tau piav qhia hauv daim duab 1.

SNCA noob hauv tib neeg muaj qhov chaw chromosomal ntawm 4q22.1, qhov ntev ntawm 114,226 lub hauv paus khub, thiab muaj rau cov exons (Touchman li al., 2001). SNCA transcription yog tswj los ntawm beta-2-adrenoreceptor (B2AR), uas tuaj yeem tiv thaiv kom muaj kev pheej hmoo ntawm PD lossis qhib kom txo tau qhov kev pheej hmoo ntawm PD (Mittal li al., 2017).

Cov qauv kev faib tawm ntawm tes ntawm ntau yam SNCA cov ntaub ntawv sau tseg ntawm tib neeg thiab cov kab mob miceare qhia hauv daim duab 2. Thawj qhov kev hloov pauv caj ces raug txheeb xyuas los cuam tshuam nrog PD yog qhov kev hloov pauv ntawm G-to-A ntawm 209thnucleotide, uas ua rau A53T kev hloov pauv ntawm SNCAgene nyob nruab nrab ntawm 4th thiab 5th rov ua dua ntawm KTEKEGV(Goedert, 1997; Polymeropoulos li al., 1997; Stefanis, 2012).

Kev hloov pauv hauv tsev neeg thiab kev nkag siab A53T muaj txiaj ntsig tau txais txiaj ntsig los ntawm kev hloov pauv hauv anautosomal tseem ceeb thiab cuam tshuam nrog kev hnav khaub ncaws-onsetnsetPD (Puschmann li al., 2009).

Hauv cov nas dopaminergic PC12 hlwb, A53T kev hloov pauv tau pom tias ua rau -synuclein ntsig txog cell tuag vim txo qis kev ua haujlwm, nce reactiveoxygen hom (ROS), nce mitochondrial permeability thiab tsis ua haujlwm, cytochrome C tso tawm, nce kev ua ntawm caspase3, caspase{{4 }}, thiab caspase-12, thiab thaum kawg, endoplasmic reticulum(ER) kev ntxhov siab vim -synuclein tsub zuj zuj hauv ER (Tanakaet al., 2001; Smith et al., 2005; Colla, 2019). SNCA noob, xws li A53T, paub tias nce tus nqi thiab qhov loj ntawm -synucleinaggregationAfterto intracell -synuclein aggregation, dopamine accumulates hauv cytoplasm, sm, thiab dopaminergictoxicity nce hauv qhov hnyav (Tabrizi li al., 2000).

Duplicationsor triplications ntawm cov tsiaj qus SNCAares kuj tseem cuam tshuam rau hauv PDpathology, PD nrog dementia, dementia nrog Lewy lub cev, thiab ntau lub cev atrophy (Book et al., 2018).

SNCA triplicationis txuas mus rau qhov pib ntxov autosomal tseem ceeb hauv tsev neeg PD thiab PD-txog kev dementia, raws li tau pom hauv Spellman-Muenterkindred, tsev neeg Swedish-American, tsev neeg los ntawm Ltalis, thiab ntau lwm tus (Singleton et al., 2003; Farrer, 40. ; Olgiatiet al., 2015; Zafar et al., 2018). Tib neeg cov neeg nqa khoom ntawm triplicatemutation ntawm SNCA muaj ob zaug ntawm kev tswj hwm qib ntawm -synucleinmRNA hauv cov ntshav thiab lub hlwb (Miller li al., 2004).

Soluble -synuclein protein ntau kuj tau muab ob npaug rau hauv cov ntshav ntawm cov neeg nqa khoom triplicate SNCA, whereas genomic triplication ntawm SNCA ua rau ntau dua ntawm insoluble -synuclein aggregates hauv lub hlwb (Miller li al., 2004).

DA neurons txawv ntawm tib neeg induced pluripotent qia hlwb (hiPSCs) los ntawm aPARK4 tus neeg mob uas tseem muaj SNCA triplication pom tau tias nce qib ntawm -synuclein piv rau kev tswj hwm hiPSC-derived DAneurons (Fukusumi li al., 2021).

Genomic duplication ntawm SNCA kuj nce -synuclein ntau ntau thiab yog ua rau cov tsev neeg PD (Chartier-Harlin li al., 2004; Ibáñez li al., 2004). Muaj kev sib raug zoo ncaj qha ntawm SNCA tus lej luam, -synuclein abundance, thiab PD phenotype hnyav (Singletonand Gwinn-Hardy, 2004). Nyob rau hauv sib piv rau triplication, cov ntaub ntawv ntawm SNCA duplication zoo li idiopathic PD nrog ib tug lig pib, thiab qeeb zuj zus, thiab yog dim los ntawm dementia (Chartier-Harlinet al., 2004; Ibáñez li al., 2004).

Txawm li cas los xij, muaj ib rooj plaub uas tau piav qhia tsis ntev los no ntawm ib tug txiv neej nrog SNCA duplication uas tau tsim tawm ntxov-onsetPD nrog kev nce zuj zus thiab kev paub sai sai (Kielb et al., 2021).Qhov txawv txav ntawm phosphorylated -synucleinto insoluble aggregate lub cev yog cov yam ntxwv ntawm Lewis. thiab yog tus txhais histopathological yam ntxwv ntawm -synucleinopathies.

Peb lub ntsiab -synucleinopathy kab mob suav nrog PD, Lewy Lub Cev Dementia (LBD), thiab ntau qhov systematrophy (MSA) (McCann li al., 2014). Cov kab mob synucleinopathy feem ntau yog PD (Grazia thiab Goedert, 2000).

Lewyneurites feem ntau muaj cov chav kawm, nyias, thiab elongated tsos (Braak li al., 1999). Lawv nyob hauv cytoplasm thiab muaj ntau dua li Lewy lub cev, tshwj xeeb tshaj yog nyob rau hauv striatumand amygdala (Volpicelli-Daley li al., 2014). Lawv kuj tau faib ntau heev hauv dorsal vagal nucleus, CA2/3 hippocampusregion, thiab nucleus basalis ntawm Meynert (Kon et al., 2020).

Lewy neurites tau pom tias ua rau tsis zoo rau kev thauj mus los ntawm axonal ntawm autophagosomes thiab endosomes uas muaj Rab7 thiab TrkBreceptors (Volpicelli-Daley li al., 2014).Lewy lub cev yog cov ntsiab lus zoo, cov protein ntau spherical conglomeratescomposed ntawm misfolded -synuclein thiab lwm yam khoom. Lawv muaj nyob rau hauv cov neeg mob PD tshwj tsis yog muaj qee tus neeg mob tshwj xeeb (Johansen li al., 2018).

Lewy lub cev nyob rau hauv lub neuronal cytoplasm thiab pom muaj faib thoob plaws hauv lub hlwb qia, limbic cheeb tsam, thiab neocortical hlwb cheeb tsam (Rezaie li al., 1996; Spillantini thiab Goedert, 2000). Lewy lub cev txuam nrog kev laus, thiab qhov hnyav ntawm Pthethe d qhov hnyav ntawm dementia (Saito li al., 2004). Ib yam li ntawd, -synuclein hauv Lewybodies yog phosphorylated thiab nitrated, qhia oxidative stressis intrinsic rau lawv tsim (Giasson li al., 2000; Fouldset al., 2011; McCormack et al., 2012; Wang et al., 2012; 2014).

Txawm hais tias dav lees paub tias yog kev txhawb nqa toneurodegeneration, muaj qee qhov kev sib cav txog seb Lewybodies ua haujlwm tiv thaiv hauv lub cell, yog tias cov txheej txheem ntawm Lewy lub cev txhawb nqa neurodegeneration, lossis yog Lewy lub cev nws tus kheej txhawb nqa neurodegeneration (Ono, 2017; Iqbal li al., 2020 ; Mahul-Mellier et al., 2020). Tag nrho peb qhov kev xav no yog qhov tseeb ib nrab.

Tsis tas li ntawd, Lewybody muaj pes tsawg leeg tau txais kev saib xyuas tshiab tsis ntev los no, qhov twg lub luag haujlwm ntawm ob qho tib si -synuclein thiab -synucleincomponents raug tshuaj xyuas. Qee qhov -synucleincomponents ntawm kev txaus siab suav nrog ubiquitin, puas organellessuch li fragmented mitochondria, thiab lipids (Nakamura li al., 2011; Lashuel, 2020).

Nws yog ib qho tseem ceeb uas yuav tsum nco ntsoov tias muaj cov pov thawj los qhia tias -synuclein tsis yog qhov muaj txiaj ntsig tshaj plaws ntawm Lewy lub cev, cuam tshuam rau cov filament-centricdogma (Lashuel, 2020). Cov proteins tsis zoo hauv cov kab mob neurodegenerative tau pom tias muaj nyob hauv ob qho tib si hauv nruab nrog cev thiab sab nraud (Peng et al. ib., 2020). Hauv PD, -synuclein aggregations tau pom ntxov tshaj plaws nyob rau hauv tus kab mob kev loj hlob mus rau hauv lub olfactory noob thiab thedorsal motor nucleus ntawm kaum cranial paj (Peng li al., 2020; Wakabayashi, 2020).

Lub pathological -synuclein ces kis rostrally los ntawm lub hlwb, midbrain, forebrain, thiab nws thiaj li mus rau lub cortex (Braak thiab Del Tredici, 2017). synuclein tau pom tias dhau ntawm cov neurons, los ntawm neuronsto microglia, los ntawm neurons mus rau astrocytes, ntawm astrocytes, thiab hla cov ntshav-hlwb barrier (BBB) ​​(Fellner li al., 2013; Loriaet al., 2017; Rostami li al., 2017. ; Bogale et al., 2021).

Microglial -Synucleinopathy hauv Parkinson's Disease

Microglia yog CNS tus neeg nyob hauv lub cev tiv thaiv kab mob macrophage uas saib xyuas kev hem thawj ntawm homeostatic thiab cuam tshuam thaum tsim nyog. Nrog rau lwm cov neeg nyob hauv glial, microglia muaj ntau haiv neeg raws li lawv qhov chaw neuroanatomical thiab ua haujlwm zoo, qhia tias lawv tau cuam tshuam los ntawm cov xwm txheej hauv cheeb tsam (Olah li al., 2011; Bachiller et al., 2018; Liand Barres, 2018; Kam et al., 2020).

Piv txwv li, microgliain noj qab nyob zoo nas basal ganglia cheeb tsam muaj cheeb tsam-specificmorphology, cell ceev, thiab suav, lysosome cov ntsiab lus thiab kev faib tawm, membrane so lub peev xwm, thiab transcriptomes (De Bias li al., 2017; Costa li al., 2021).

Tsis tas li ntawd, microgliaexperience tau hloov pauv cov qib intracellular -synuclein raws li lawv ib puag ncig, xws li teb rau cytokines orcerebrospinal kua (CSF) los ntawm cov neeg mob PD (Bick et al., 2008; Schiess et al., 2010).

Substantia nigra pars compacta (SNpc) microglia txawv ntawm microglia hauv thaj chaw ventral tegmental (VTA) (Shaerzadehet al., 2020). Tej zaum qhov sib txawv hauv cheeb tsam microglial tuaj yeem piav qhia txog PD cuam tshuam txog kev poob ntawm dopaminergic neurons hauv SNpc, dua li hauv VTA. Cov laj thawj rau qhov kev xaiv hauv cheeb tsam no ntawm dopaminergic neuronal poob tseem tsis tau nkag siab (Krashia li al., 2019; Shaerzadeh li al., 2020).

Txawm li cas los xij, nws zoo li qhov kev xav tsim nyog uas microglial activation muaj lub luag haujlwm ua si. Piv txwv li, nas overexpressing wildtype human-synuclein thoob plaws hauv CNS tau nce qib ntawm activated microglia thiab TNF-alpha hauv striatumas thaum ntxov li 1 lub hlis thiab tom qab ntawd cov substantia nigra asearly li 5 lub hlis, tab sis tsis nyob rau hauv lwm qhov chaw ntawm lub hlwb (Watsonet al. , 2012).

Lub cheeb tsam tshwj xeeb qhib microglial teb kom nce qib ntawm -synuclein txuas ntxiv mus ntev li kev soj ntsuam tau tshwm sim, dhau 14 lub hlis (Watson li al., 2012). Hauv humanPD cov neeg mob, PET imaging thiab postmortem hlwb tsom xam pom lub regional activated microglial hlwb nyob rau hauv lub midbrain, thefrontal cortex, thiab lub cev nqaij daim tawv (Gerhard li al., 2006; Garcia-Esparcia li al., 2014).

Ob leeg 1-Methyl-4-phenyl-1, 2,3, 6-tetrahydropyridine (MPTP) thiab -synuclein over-expressionmodels ntawm PD hauv cov liab kuj pom cov cheeb tsam tshwj xeeb thiab mus sij hawm ntev microglial activation hauv SNpc (Kanaan li al., 2008; Barkholt li al., 2012).

Yog li ntawd, elevated -synucleinlevels ua rau microglia sai sai thiab pheej ua haujlwm, uas ua rau muaj zog neuroinflammatory secretions los ntawm microglia.

Ntawm cov hauv vitro thiab hauv vivo qauv ntawm PD, -synuclein ua rau microglia ua kom nrawm nrawm, txav mus rau -synuclein qhov chaw thiab tom qab ntawd nce phagocytic thiab proinflammatory (Zhang li al., 2005; Su et al., 2008; Wang et al. , 2015; Mavroeidi thiab Xilouri, 2021).

Extracellular synuclein raug tshem tawm los ntawm kev ua kom microglial engulfing thiab autophagy, kho los ntawm TLR4-NF-kB signaling nyob rau hauv ib tug txheej txheem tsis ntev los no nrhiav tau thiab coined li "synucleinphagy" (Choi et al., 2020).

Txawm li cas los xij, kev ua haujlwm ntawm microglial phagocytic yog txo qis (Bliederhaeuser li al., 2016). Cov theem ntawm microglial activation yog ntau dua nyob rau hauv lub xub ntiag ntawm -synuclein mutants piv rau towild-type -synuclein protein, tej zaum xav txog qhov hnyav ntawm lawv cov kab mob ntsig txog (Roodveldt li al., 2010; Hoenen li al., 2016).

Tseeb, qhov kev hloov pauv ntawm PD-txog -synucleinA53T tau pom tias yuav ua rau muaj kev loj hlob ntawm microglial CXCL12 hauv kab lis kev cai ntawm tes thiab nas SNpc (Li et al., 2019). Postmortem hlwb cov ntaub so ntswg ntawm PD cov neeg mob kuj qhia ncaj qha correlation ntawm -synuclein thiab CXCL12 theem (Li li al., 2019).

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