Periphery And Brain, Innate And Adaptive Immunity in Parkinson's Disease Part 2

Adaptive immunity in Parkinson's disease: HLA thiab T hlwb

Phagocytosis ntawm -syn yuav coj cov protein mus rau MHC encoded los ntawm HLA-system (Fig. 1). HLA yog ib pawg noob caj noob ces uas tau muab faib rau hauv chav kawm I (MHCI) thiab chav kawm II cheeb tsam (MHCII), ob qho tib si nyob rau ntawm chromosome 6. Cov noob no yog qhov tseem ceeb rau kev sib txuas cov kab mob hauv lub cev thiab yoog raws cov lus teb thiab yog lub luag haujlwm rau kev xaiv T cell, kuaj cov tshuaj antigen. , activation, thiab induction ntawm adaptive immune teb. Txuas cov noob caj noob ces rau PD kev pheej hmoo, GWAS tau cuam tshuam ib leeg nucleotide polymorphisms (SNPs) hauv HLA-DR uas cuam tshuam nrog kev pib lig idiopathic PD, qhia txog lub luag haujlwm rau lub cev tiv thaiv kab mob hauv PD susceptibility [75]. SNPs hauv HLA-DR yog txuam nrog lwm yam kab mob autoimmune xws li mob caj dab rheumatoid, ntau yam sclerosis, thiab kab mob plab hnyuv (IBD).

Txij li thaum pib GWAS, cov txiaj ntsig no tau rov ua dua los cuam tshuam ntau yam MHCII alleles suav nrog HLA-DRB5 * 01 thiab HLADRB1 * 15: 01 [188]. Cov SNPs no nyob hauv thaj tsam tsis-coding ntawm HLA [75, 188] qhia tias lawv yuav cuam tshuam rau MHCII kev qhia, uas tau lees paub tias yuav siab dua hauv PBMCs cais los ntawm SNP-carrying PD cov neeg mob [94].

Lub cev tiv thaiv kab mob yoog tau tuaj yeem paub thiab tua ntau yam kab mob xws li kab mob, kab mob, thiab fungi. Nws feem ntau yog tsim los ntawm T hlwb thiab B hlwb, uas tuaj yeem paub txog cov kab mob tshwj xeeb thiab tso cov tshuaj tiv thaiv kab mob los yog tsim cov hlwb kom tua cov kab mob tib yam sai dua thiab ua tau zoo thaum lwm zaus nws ntsib. Los ntawm qhov kev xav no, kev hloov pauv ntawm lub cev tiv thaiv kab mob thiab kev tiv thaiv kab mob yog ob yam tseem ceeb ntawm tib neeg lub cev tiv thaiv kab mob, thiab lawv muaj kev sib raug zoo thiab cuam tshuam rau ib leeg. Yog li ntawd, nyob rau hauv peb lub neej txhua hnub, peb yuav tsum tau xyuam xim rau kev txhim kho peb kev tiv thaiv. Peb pom tias Cistanche tuaj yeem txhim kho kev tiv thaiv. Cistanche yog nplua nuj nyob rau hauv ntau yam antioxidants, xws li vitamin C, vitamin C, carotenoids, thiab lwm yam. Cov khoom xyaw no tuaj yeem tshem tawm cov dawb radicals thiab txo Oxidative kev nyuaj siab, txhim kho kev tiv thaiv ntawm lub cev.

Nyem qhov txiaj ntsig kev noj qab haus huv ntawm cistanche

Hauv CNS, MHCII cov protein tau nthuav tawm ntawm cov kab mob antigen-presenting (APCs) xws li CNS cov neeg nyob hauv microglia thiab ciam teb cuam tshuam nrog macrophages, thiab hauv peripheral infiltrating monocytes thiab monocyte-derived macrophages. Hauv postmortem PD lub hlwb, HLA-DR ntxiv cov hlwb raug kuaj pom ze neurons nrog -syn pathology [35] hauv SN [123] nrog rau CD4 ntxiv thiab CD8 ntxiv rau T hlwb nyob ib puag ncig neuromelanin ntxiv rau neurons [16].

Ntxiv mus, HLA-DR kev qhia hauv CNS cuam tshuam nrog cov kab mob hnyav [89], qhia tias kev nthuav qhia antigen thiab hloov lub cev tiv thaiv kab mob yog qhov tseem ceeb rau neurodegeneration. Hauv -syn kab mob-vector-raws li tsiaj qauv ntawm PD, reactive MHCII ntxiv rau microglia [9, 77, 150], as Well as infiltrating monocytes / macrophages [78, 79] thiab T hlwb, tau tshaj tawm [78, 148, 150 ib., 186]. Genetic deficiency ntawm MHCII [77], MHCII transcriptional coactivator CIITA [186], thiab CD4 (Harms li al., unpublished) yog neuroprotective qhia lub luag haujlwm tseem ceeb ntawm CNS antigen nthuav qhia rau CD4 T hlwb hauv neurodegeneration.

Thaum tsis muaj feem cuam tshuam rau hauv kev tshawb nrhiav caj ces, kev tshawb fawb hauv cov ntaub so ntswg tom qab kuj tau qhia txog MHCI ntawm cov neurons hauv SN thiab locus coeruleus ntawm PD cov neeg mob thiab nyob ze CD8 ntxiv rau T hlwb [25]. Interestingly, cov neurons no yog IFN- teb thiab upregulate functional MHCI ntawm lub xovtooj ntawm tes, nquag nthuav tawm antigens rau CD8 T hlwb, implicating ib tug tshiab mechanism ntawm selectively neuronal vulnerability nyob rau hauv PD [25].
Raws li tau hais, hauv postmortem PD lub hlwb, CD4 ntxiv thiab CD8 ntxiv rau T hlwb tau kuaj pom hauv SN [16, 162] nyob ze cov hlab ntsha thiab ib puag ncig neuromelanin ntxiv rau neurons [16] qhia txog lub luag haujlwm rau T hlwb hauv PD pathogenesis. Kev sib cuam tshuam ntawm MHCII ntxiv rau -APC yog qhov tseem ceeb thiab lub luag haujlwm rau nce T cell derived-cytokine qhia, tshwj xeeb yog IFN- thiab TNF, hauv lub hlwb, ntshav, thiab CSF pom hauv PD [13, 187].

Hauv kev txhawb nqa ntawm T hlwb tsav o hauv PD, ntau cov kev tshawb fawb ntau xyoo tau tshaj tawm cov kev hloov pauv hauv T cell subsets, qhov tseem ceeb txo qis hauv naïve, CD4 T pab hlwb (Th), cytotoxic T hlwb (CD8), thiab T regulatory (Treg) cov hlwb thaum lwm tus tau tshaj tawm tias tsis muaj kev hloov pauv lossis nce hauv tag nrho cov lej (saib hauv [59]). Qhov kev txo qis hauv PD tsis ntev los no tau cuam tshuam nrog kev txo qis hauv Th2, Th17, thiab kev tswj hwm T-cell pejxeem; Tsis tas li ntawd, CD4-Th hlwb los ntawm PD cov neeg mob qhia ib qho Th1- cov tshuaj tiv thaiv kab mob tsis txaus ntseeg nrog nce IFN- thiab TNF ntau lawm [108]. Txawm li cas los xij, lwm txoj kev tshawb fawb tsis ntev los no los ntawm Sommer et al. pom kev nce ntxiv hauv Th17 hlwb hauv PD txheeb ze rau kev tswj hwm thiab kev tshawb fawb soj ntsuam siv cov Th17 hlwb qhia IL-17A los ntawm PD cov neeg mob tau muaj kev cuam tshuam ncaj qha rau iPSC-derived neurons qhia IL-17R, tawm tswv yim Th17 hlwb tej zaum yuav yog tus tswj ntawm dopaminergic neuronal ciaj sia nyob rau hauv ib qho kev sim qauv ntawm PD [162]. Zuag qhia tag nrho, cov kev tshawb pom no qhia tias tsis muaj qhov sib npaug hauv Th hlwb ntawm cov pro-inflammatory phenotypes, uas tuaj yeem ua rau muaj kev cuam tshuam rau neurodegeneration.

Kev tshawb fawb tam sim no qhia tau hais tias nws yuav tsis tas yuav yog tus lej ntawm T cell subsets, tab sis cov nyhuv (Tef) cov lus teb uas ua rau mob PD. Tib neeg cov kev tshawb fawb tau pom tsis muaj qhov hloov pauv hauv Treg cov lej, tab sis qhov txo qis hauv Treg lub peev xwm los cuam tshuam cov kev ua ntawm Tef hlwb [153] hauv vitro, qhia txog kev txo qis hauv kev tswj cov lus teb hauv PD. Tsis tas li ntawd, peb tau pom tias nyob rau hauv vivo T hlwb hnov ​​txawv txawv rau peripheral txhaj tshuaj ntawm monomeric thiab hloov kho -syn (fibrillar los yog nitrated), thiab cov conformer-responsive T hlwb ua hauj lwm rau modulate microglia nyob rau hauv lub hlwb [130].

Tsis tas li ntawd, peb kuj tau tshaj tawm tias hauv -syn AAV2/5 nas PD qauv, Treg hlwb zoo li qhov tseem ceeb hauv kev hloov kho cov kab mob phenotypes raws li kev txhaj tshuaj tiv thaiv Treg cov neeg nyob rau hauv periphery [33], nce tus naj npawb ntawm Treg hlwb hauv lub hlwb thiab txo qis - syn pathology [148], qhia T cell-modulation raws li lub peev xwm tiv thaiv lub tswv yim.

Hauv kev txhawb nqa ntawm T hlwb ua rau mob, ib qho kev tshawb fawb tseem ceeb los ntawm Sulzer thiab cov npoj yaig tau pom tias PBMCs tau los ntawm PD cov neeg mob tau teb rau -syn peptide fragments [166] txhawb nqa antigenicity ntawm -syn, qhov kev tshawb pom uas tau rov ua dua [115]. Lawv txoj hauv kev tau pom tias -syn-derived epitopes, tshwj xeeb tshaj yog cov epitopes hauv thaj av pSer129 (koom nrog Lewy lub cev) tau lees paub feem ntau los ntawm CD4 ntxiv rau T hlwb, thiab los ntawm CD8 ntxiv, txawm tias tsawg dua [166].

Interestingly, ib qho tshwj xeeb T cell activating peptide fragment tau pom tias khi nrog siab affinity rau HLA alleles DRB5 * 01 thiab DRB1 * 15: 01, ntxiv dag zog rau lub luag haujlwm ntawm -syn-tsav antigen kev nthuav qhia thiab tom qab hloov kho lub cev tiv thaiv kab mob [166]. Hauv kev tshawb nrhiav tom qab, cov kws sau ntawv tau pom tias -syn reactivity hauv T-cells tshwm sim ua ntej kuaj kab mob thiab tshwj xeeb tshaj yog thaum ntxov ntawm tus kab mob thiab txo qis tom qab, tseem ceeb dua qhov tseem ceeb ntawm cov kab mob theem hauv lub cev tiv thaiv kab mob [ 113] ib. Qhov zoo siab, -syn reactive T-hlwb tso tawm IFN- thiab IL-4, cuam tshuam nrog Th1 thiab Th2 cov lus teb, feem. Txawm li cas los xij, lawv kuj tau tso tawm IL-10, ib qho tshuaj tiv thaiv kab mob cytokine, txawm tias tsis qhia cov cim ntawm Treg hlwb [113], uas txhawb nqa qhov kawg ntawm kev muaj peev xwm tiv thaiv kab mob thaum tus kab mob loj tuaj. Cov kev tshawb fawb yav tom ntej yog qhov tseem ceeb los txiav txim siab qhov kev loj hlob zoo ntawm T cell teb, thiab seb cov tshuaj tiv thaiv kab mob T cell lub hom phiaj puas yog kho kab mob hauv PD.

Humoral teb: B hlwb thiab autoantibodies

Thaum B hlwb pab txhawb rau CNS kab mob los ntawm lawv cov kev ua nyob rau hauv lub periphery, kev tshawb fawb rau lub luag hauj lwm ntawm B hlwb nyob rau hauv PD rau hnub no tau txwv [146]. Hauv cov xwm txheej tsis tu ncua, B hlwb muaj nyob hauv CNS parenchyma hauv cov lej qis (~0.1 cell/cm2) thiab qhov chaw perivascular [5], thiab cov subset ntawm B hlwb tuaj yeem nce ntau thiab / lossis effector muaj nuj nqi [105, 119]. Qhov B cell muaj nyob rau hauv CNS-cuam tshuam qhov chaw qhia txog lub luag haujlwm rau B hlwb hauv kev tiv thaiv kab mob thiab kev nco txog antigen thiab tseem cuam tshuam txog cov kab mob uas yuav cuam tshuam los ntawm hnub nyoog thiab cov kab mob neurodegenerative [146].

Hauv PD, B hlwb tsis tau kuaj pom hauv lub hlwb postmortem, txawm li cas los xij, cov deposits ntawm IgG tau kuaj pom ntawm dopaminergic neurons hauv SN thiab Lewy lub cev hauv CNS [131]. Hauv kev txhawb nqa ntawm cov hnub nyoog ntsig txog phenotypes hauv PD, nws tau pom tias autoantibodies txo qis hauv PD, qhia txog lub luag haujlwm tiv thaiv B hlwb los ntawm kev muab cov ntsiab lus ntawm extracellular clearance ntawm pathological -syn [10, 19]. Lwm cov kev tshawb fawb tau pom muaj cov tshuaj tiv thaiv kab mob siab-syn hauv cov ntawv qub ntawm PD [134], lossis hauv cov PD hauv cov ntshav [159] thiab CSF [3, 86]. Cov txiaj ntsig tsis sib haum no tau raug tshuaj xyuas tsis ntev los no hauv kev tshuaj ntsuam meta, qhov twg cov kws sau ntawv xaus lus tias qhov sib txawv ntawm pawg, kev tswj hwm, thiab cov txheej txheem thev naus laus zis tuaj yeem suav rau qhov tsis sib xws [158]. Txawm hais tias nws tseem tsis tau paub meej tias cov neeg mob tau txais los ntawm cov tshuaj tiv thaiv - -syn antibodies yog cov tshuaj tiv thaiv kab mob neuroprotective los yog tsis, raws li kev soj ntsuam hauv vitro qhia tias cov tshuaj tiv thaiv pab rau -syn clearance [8], thiab qhov no kuj tau txais kev txhawb los ntawm hauv vivo kev tshawb fawb [47 ], uas tau coj mus rau qhov kev sim tshuaj niaj hnub niaj hnub no siv kev txhaj tshuaj tiv thaiv kab mob tsis zoo thiab nquag.

Soluble immune biomarkers-predictors ntawm tus kab mob tshwm sim?

Vim muaj kev nkag mus tau ntawm peripheral biofluids, nws tau npaj siab tias cov tshuaj tiv thaiv kab mob tiv thaiv kab mob tuaj yeem tso cai rau kev kuaj mob ntxov thiab kev ntsuas tus kheej ntawm tus kab mob. Ntau lub chaw kuaj mob tau tshaj tawm txog kev hloov pauv hauv cytokine thiab chemokine qauv hauv PD tus neeg mob biofluids (Table 2). Ob qhov kev ntsuam xyuas tsis ntev los no tau tshaj tawm txog kev nce ntxiv hauv ntau qhov kev tiv thaiv kab mob cytokines thiab lwm cov kab mob tiv thaiv kab mob hauv CSF thiab cov neeg mob ntshav qab zib PD, qhia txog kev tswj hwm kev tiv thaiv kab mob tshwm sim nyob rau hauv tib lub sijhawm hauv lub hlwb thiab sab hauv [102, 141] ib.

tshwm sim nyob rau hauv parallel nyob rau hauv lub hlwb thiab periphery [102, 141]. Kev txheeb xyuas qhov mob hauv PD thiab nws lub luag haujlwm tsis zoo, qhov nce hauv C-reactive protein (CRP), ib qho mob hnyav theem protein, tuaj yeem kwv yees kev paub tsis meej [125] thiab PD prognosis [154] thiab cuam tshuam rau cov tsos mob hnyav hauv cov neeg mob PD [ 151] ib. Tsis tas li ntawd, "pro-inflammatory profile" pom nyob rau hauv cov ntshav ntawm cov neeg mob PD tshiab (Table 2) tau cuam tshuam nrog cov qhab nia qis zog thiab kev poob qis dua [187]. Raws li, kev siv cov tshuaj tiv thaiv TNF muaj feem xyuam rau qis dua PD tshwm sim [138] thiab kuj tau pom tias muaj cov nyhuv neuroprotective hauv PD qauv [122]. Lwm txoj kev tshawb fawb hauv cov neeg mob uas muaj PD thaum ntxov tau pom tias nce qib ntawm IL-1 , IL-2, thiab IL{14}} hauv cov ntshav (vs. tswj) [101]. IL-2 kuj tau nce siab hauv lub hlwb ntawm cov neeg mob PD [145], uas yog qhov tshwj xeeb, vim nws lub luag haujlwm tseem ceeb hauv T-cell ciaj sia taus thiab ua kom muaj zog.

Qhov nce hauv IL-1 qib hauv PD cov neeg mob txhawb kev cuam tshuam ntawm inflammasome kuj tau qhia los ntawm NLRP3 nce hauv cov ntshav [29] thiab lub hlwb ntawm cov neeg mob PD [112]. Nce NLRP3 protein ntau ntau, caspase-1, thiab IL-1 tau pom nyob rau hauv PBMCs los ntawm PD cov neeg mob qhov twg, ib zaug ntxiv, plasma qib ntawm IL-1 tau nce thiab cuam tshuam nrog lub cev muaj zog hnyav. -syn qib hauv cov ntshav kuj tseem ceeb dua hauv cov neeg mob PD thiab cuam tshuam nrog cov qhab nia ntawm lub cev muaj zog thiab IL-1 qhia [49]. Hauv qhov sib piv, ib txoj kev tshawb fawb tsis ntev los no tau tshaj tawm qis dua -syn thiab caspase-1 qib hauv PD serum vs. tswj [185]. Txawm hais tias cov txiaj ntsig tsis sib xws, ob qho kev tshawb fawb pom muaj kev sib raug zoo ntawm -syn thiab caspase-1 txhawb nqa kev sib raug zoo ntawm -syn hauv inflammasome cascade, uas yuav tsum tau tshawb fawb ntxiv.

Txhawb nqa lub luag haujlwm tsis zoo hauv kev nrhiav neeg lub cev tiv thaiv kab mob, ntau qhov kev tshawb fawb qhia tias cov tshuaj chemokines tshwj xeeb tshaj yog cuam tshuam rau PD kev nce qib thiab hauv cov ntawv PD ntau dua. Raws li, nyob rau hauv ib tug longitudinal txoj kev tshawb no, CCL3 (MIP1) thiab CCL2 yog cov serum biomarkers pab txhawb ntau tshaj rau cov qauv kev kwv yees ntawm lub cev muaj zog hnyav [2]. Thiab qhov tseeb, hauv CSF ntawm cov neeg mob PD, kev nce hauv T hlwb thiab cov monocytes uas tsis yog classical tau raug pom, nrog rau qib siab ntawm pro-inflammatory cytokines thiab CCL2 [157].

Tsis tas li ntawd, chemokines IL-8, CCL2, thiab CCL4 yog qhov tshwj xeeb tshaj yog muaj feem cuam tshuam rau PD subtypes xws li hauv PD-LRRK2 cov neeg mob uas muaj diffuse / malignant PD [17], thiab hauv GBA-PD, qhov twg IL-8 tau sib raug zoo nrog kev paub ntau dua [27]. Monocyte activation zoo nkaus li muaj feem cuam tshuam tshwj xeeb hauv kev paub txog ntawm PD. Raws li, PD cov neeg mob uas muaj kev pheej hmoo siab dua los tsim cov tsos mob ntawm kev txawj ntse, pom ntau qhov kev hloov pauv tseem ceeb hauv cov pej xeem monocytic [185]. Ntxiv mus, peb tau pom tias cov kuab tshuaj CD163, uas tsuas yog tsim los ntawm monocytes / macrophages thaum lub sijhawm ua haujlwm, tau nce hauv PD CSF thiab cuam tshuam ncaj qha nrog -syn thiab tsis ncaj nrog cov qhab nia kev txawj ntse [127]. Yog li, ntau dua monocytic activation tau txuam nrog kev paub tsis zoo. Tsis tas li ntawd, nyob rau hauv PD nrog dementia, qib ntawm kev tiv thaiv kab mob, kev soj ntsuam los ntawm PK11195 PET tau cuam tshuam nrog cov qhab nia qis [46]. Yog li, cov tshuaj tiv thaiv kab mob zoo li pom tau yooj yim dua nyob rau hauv cov xwm txheej uas qhov kev kawm ntawm PD kev loj hlob yog nruj thiab cuam tshuam nrog kev paub tsis meej.

Vagus paj hlwb, plab, thiab peripheral o

Braak hypothesis qhia tias -syn-pathology thiab PD yuav pib nyob rau hauv lub periphery nyob rau hauv lub plab hnyuv ib ntsuj av, thiab los ntawm lub vagus paj hlwb thiab dorsal motor nucleus (DMN) nce mus rau lub hlwb; Yog li ntawd, pathology pom nyob rau hauv peripheral paj hlwb (PNS) thiab CNS. Tseeb tiag, peripheral denervation txuam nrog cov paj hlwb vagus tau pom hauv PD (saib hauv [15]). Qhov no yuav muaj qhov cuam tshuam ncaj qha rau ntawm lub cev tiv thaiv kab mob, tshwj xeeb los ntawm qhov hu ua inflammatory reflex: ib qho kev sib txuas lus ntawm lub hlwb-kev sib txuas lus uas txuas rau ntawm DMV thiab acetylcholine signaling. Qhov no suav nrog tus po, plab, T-hlwb, macrophages, thiab ntau lub paj hlwb (saib hauv [30]). Borghammer et al. Tsis ntev los no tau tshaj tawm qhov kev xav tshiab ntawm ob PD subtypes raws li seb cov neeg mob puas pom thawj cov tsos mob ntawm neurodegeneration: hauv PNS, lub cev-thawj-PD, lossis CNS: hlwb-thawj-PD [85].

Raws li, nyob rau hauv nas -syn raws li qauv, -syn pathology tuaj yeem kis tau ob txoj kev ntawm lub plab-hlwb [174, 175]. Thaum lub cev xav tau thawj zaug qhia pom RBD cov tsos mob, kev loj hlob sai, thiab ntau dua kev paub tsis meej, lub hlwb-thawj yog RBD-tsis zoo thiab qhia tau tias muaj kab mob me me. Nyob rau hauv lub teeb ntawm Borghammer txoj kev xav, thawj myeloid cell mus ntsib aggregated -syn yuav peripheral monocytes thiab macrophages nyob rau hauv lub cev-thawj hom PD, vs. microglia nyob rau hauv lub hlwb-thawj-PD subtype. Tsis tas li ntawd, kev poob ntawm kev tiv thaiv kab mob los ntawm DMN yuav tshwm sim thaum ntxov ntawm lub cev-thawj-PD, uas yuav ua rau muaj kev loj hlob sai thiab hnyav dua ntawm cov kab mob no. Raws li, cov neeg mob RBD (putative body-first-PD) qhia qhov txo qis hauv cov tshuaj tiv thaiv kab mob cytokine IL-10, tsis yog cov pro-inflammatory profile, uas tej zaum yuav cuam tshuam rau DMN kev hlub [100].

Raws li qhov txiaj ntsig ncaj qha ntawm qhov kev tshawb pom ntawm PNS degeneration hauv PD, kev tshawb fawb txog lub plab-hlwb axis thiab microbiota cuam tshuam hauv neurodegeneration tau txaus siab. Interestingly, nyob rau hauv lub rAAV- -syn nas qauv, overexpression ntawm -syn nyob rau hauv lub SN coj mus rau enteric paj hlwb hloov thiab altered microbiota [129], thaum nyob rau hauv lub transgenic -syn PD qauv, lub microbiota cuam tshuam cov txheej txheem neurodegeneration [ 147] ib. Qhov tseeb, kev hloov pauv hauv microbiota tau cuam tshuam nrog PD [167], tab sis kuj rau RBD, qhia tias qhov no yuav yog qhov tseem ceeb ntawm qhov tseem ceeb heev [81]. Kev cuam tshuam ntawm microbiota ntawm kev txhim kho lub cev tiv thaiv kab mob tau paub ntev, tab sis qhov no yog lub tswv yim tshiab tshiab hauv PD teb (saib hauv [88]). Qhov cuam tshuam ntawm kab mob plab kuj tau raug tshawb xyuas hauv kev tshawb fawb txog kev kis kab mob uas qhia tias qhov kev pheej hmoo thiab qhov tshwm sim ntawm PD yog qis dua rau cov neeg uas tau mus rau vagotomy lossis appendectomy ua ntej hauv lub neej [168, 169]. Nyob rau hauv cov ntsiab lus no, inflammatory txheej xwm nyob rau hauv lub digestive raj (xws li nyob rau hauv daim ntawv ntxiv) zoo li muaj feem xyuam rau, tshwj xeeb tshaj yog vim lub enrichment ntawm -syn ntawm lub myenteric plexus ntawm lub appendix thiab lub xub ntiag ntawm macrophages nrog engulfed -syn nyob rau hauv lub cheeb tsam [66. ]. Qhov no kuj tau txais kev txhawb nqa los ntawm kev sib raug zoo ntawm PD nrog IBD [18]. Kev mob plab thiab dysbiosis yuav ua rau lub plab hnyuv phab ntsa uas yuav ua rau lub cev tsis muaj zog uas txhawb nqa neurodegeneration (Daim duab 1).

Ib txoj kev tshawb fawb tsis ntev los no tau pom tias muaj ntau theem ntawm endotoxin hauv PD cov neeg mob cov ntshav, tshwj xeeb tshaj yog cov neeg uas muaj kev pheej hmoo siab rau dementia, qhia txog lub luag haujlwm tseem ceeb ntawm cov kab mob hauv qhov tshwm sim ntawm tus kab mob [185]. Qhov no yog nyob rau hauv kev pom zoo nrog cov synergistic neurotoxic nyhuv ntawm ntev (peripheral) LPS thiab -syn qhia los ntawm Hong's lab [56, 193]. Interestingly, ib txoj kev tshawb no nyob rau hauv WT nas pom tau hais tias intraperitoneal LPS txhaj tshuaj, ua ntej -syn peripheral intravenous tswj, coj mus rau -syn internalization los ntawm inflammatory monocytes uas nyob rau hauv lem yuav infiltrate lub hlwb, qhia hais tias lub peripheral activated monocytes yuav ua tau raws li ib tug Trojan nees nyob rau hauv PD. , txhawb kev nkag ntawm peripheral (hloov) -syn rau hauv CNS [137]. Ua ke qhov no tau pab txhawb rau qhov kev xav ntawm ob tog ntawm PD thiab ntxiv corroborates lub complex thiab multisystem xwm ntawm PD (saib [92]).

Lwm yam cuam tshuam nrog -synuclein thiab lub cev tiv thaiv kab mob hauv Parkinson tus kab mob

Lysosomal dysfunction zoo li yog nyob rau hauv nruab nrab ntawm -syn pathology, ib tug txheej txheem ntawm tshwj xeeb qhov tseem ceeb nyob rau hauv glia (saib xyuas [52]); Nyob rau hauv tas li ntawd, peb yuav luv luv tham txog ob proteins uas muaj feem xyuam rau PD: LRRK2 thiab glucocerebrosidase (Gcase). LRRK2 tau hais tawm hauv lub cev tiv thaiv kab mob, tab sis muaj ntau dua hauv monocytes thiab microglia dua li hauv T hlwb [58], qhia tias LRRK2 yog ib qho tseem ceeb hauv kev tiv thaiv innate. Cov kev tshawb fawb genomic cuam tshuam txog kev hloov pauv LRRK2 tsis yog hauv PD nkaus xwb tab sis kuj muaj lwm yam kab mob inflammatory, tshwj xeeb yog IBD, ntxiv rau kev txhawb nqa lub luag haujlwm ntawm LRRK2 hauv lub cev tiv thaiv kab mob [179]. Nyob rau hauv lub cell, LRRK2 tau cuam tshuam rau hauv phagocytosis los ntawm txoj kev autophagy/lysosomal degradation txoj kev [155], thiab LRKK2 kev hloov ua rau qhov txawv txav ntawm chaperone-mediated autophagy thiab -syn txuam nrog [82]. Rab proteins tau raug txheeb xyuas tias yog cov substrates rau LRRK2 kinase kev ua haujlwm [114, 143], cuam tshuam lub luag haujlwm rau LRRK2 hauv cov khoom siv membrane thiab kev tswj hwm lub cev tiv thaiv kab mob xws li phagocytosis, exocytosis, thiab kev nthuav qhia antigen. LRRK2 kuj tseem cuam tshuam rau hauv kev hloov pauv ntawm cov cim ntawm tes-nto hauv monocytes thiab microglia [172] thiab kev tswj hwm ntawm cytokine ntau lawm [124], thiab cov kab mob hloov pauv tau cuam tshuam nrog kev txhim kho neuroinflammation thiab neurodegeneration raws li kev mob o [106].

Raws li tau hais, lub cev tiv thaiv kab mob yuav teb rau -syn txhawb o thiab protein clearance / degradation. Ob qhov txheej txheem no yuav raug kho los ntawm LRRK2, vim yog txoj hauv kev receptor ntau (rau ob qho tib si -syn thiab LRRK2), lossis los ntawm LRRK2- kho kom haum rau autophagy degradation [37]. Pathogenic mutations ntawm LRRK2 zoo li cuam tshuam microglia lub peev xwm rau sab hauv thiab degrade -syn [99]. Tsis tas li ntawd, LRRK2 qhia thiab phosphorylation nce hauv microglia thiab monocytes raws li TLR2 lossis TLR4 stimulation [124, 155], ob leeg -syn interactors. Txawm hais tias LRRK2 cov lus teb txawv me ntsis hauv monocytes vs. microglia cell kab, ob qho tib si pom autophagic deficits raws li LRRK2 knock-down [155], ntxiv cuam tshuam LRRK2 hauv kev tswj hwm ntawm lysosomal degradation hauv myeloid hlwb. Hauv kev tshawb fawb tib neeg, ob qho tib si asymptomatic thiab PD tus neeg mob nqa khoom ntawm LRRK2 G2019S kev hloov pauv pom tau nce qib ntawm peripheral inflammatory cytokines [43], qhia txog kev pab cuam ntawm LRRK2 kev hloov pauv hauv kev sib haum xeeb peripheral tiv thaiv kab mob. Ua ke, qhov no qhia tau hais tias kev tsis sib haum xeeb ntawm cov no thiab lwm yam LRRK2-txoj kev taw qhia kev sib txuas yuav cuam tshuam rau -syn tsub zuj zuj thiab qhov tshwm sim neuroinflammation. Rau kev nyeem ntxiv txog lub luag haujlwm ntawm LRRK2 hauv kev tiv thaiv kab mob, peb xa tus nyeem ntawv mus rau [22, 179].

Kev hloov pauv hauv GBA1 noob, encoding lysosomal enzyme Gcase yog lub luag haujlwm ua rau autosomal lipid cia teeb meem, Gaucher kab mob (GD), tus cwj pwm los ntawm kev tso tawm ntawm glucocerebrosides hauv monocytes-macrophages. GBA1 kev hloov pauv yog qhov tseem ceeb tshaj plaws ntawm kev pheej hmoo ntawm caj ces rau PD [161]. Postmortem tsom xam ntawm cov ntaub so ntswg hlwb los ntawm cov neeg mob nrog GBA-PD pom tau tias nce qib ntawm -syn nyob rau hauv SN thiab ib tug tseem ceeb correlation ntawm qhov txo nyob rau hauv Gcase protein ntau ntau thiab nce nyob rau hauv p129 / tag nrho -syn [69]. Tseeb tiag, kev sib txuas ntawm biochemical ntawm GBA thiab -syn tau tshaj tawm, nrog GBA kev hloov pauv ua rau kev sib sau ntawm -syn hauv tib neeg lub hlwb [36] thiab -synuclein pathology hauv cov qauv nas, cuam tshuam nrog autophagy tsis ua haujlwm [152]. Tsis tas li ntawd, -syn pathology nws tus kheej tuaj yeem ua rau lysosomal dysfunction [121]. Yog li, cov txiaj ntsig ntxiv ntawm GBA kev hloov pauv ntawm lysosomal tsis ua haujlwm thiab lipid tsub zuj zuj tuaj yeem piav qhia qhov kev pheej hmoo siab dua PD pom. Remarkably, GBA cov neeg nqa khoom uas tsis tau pom PD qhia txog kev tiv thaiv kab mob los ntawm PK1195 PET hauv SN [126], txhawb nqa lub luag haujlwm thaum ntxov hauv kev tiv thaiv kab mob.

Interestingly LRRK2 thiab GCase zoo li converge txij li thaum LRRK2 kev hloov pauv tau ua rau txo qis GCase hauv cov neeg mob tau txais cov hlwb, thiab inhibition ntawm LRRK2 kinase kev ua kom GCase kev ua haujlwm hauv neurons nrog LRRK2 lossis GBA1 kev hloov pauv.[191]. Raws li, kev ua haujlwm ntawm GCase tuaj yeem cawm neuronal noj qab haus huv hauv iPSC qauv ntawm genetic GBA thiab LRRK2 PD [20]. Gcase kuj tseem muaj kev tiv thaiv hauv tus qauv ntawm peripheral synucleinopathy raws li kev txhaj tshuaj ntawm -syn PFF hauv plab, txhawb qhov tseem ceeb ntawm kev ncaj ncees ntawm lysosomal muaj nuj nqi hauv peripheral pathology hauv PD [28]. Raws li, Gcase kev ua tau pom tau txo qis hauv monocytes los ntawm cov neeg mob idiopathic PD [6] ntxiv txhawb kev ua haujlwm ntawm lysosomal hauv peripheral myeloid hlwb. Nyob rau hauv monocyte-derived macrophages los ntawm cov neeg mob uas muaj hom 1 GD, inflammasome activation tau tshwm sim los ntawm impaired lysosomal autophagy [1]. Hauv cov hlwb no, qhov nce hauv p62 coj mus rau kev ua kom muaj p65-NFκB txoj hauv kev, uas tau txhawb nqa qhov kev qhia ntawm inflammatory cytokines thiab nce IL-1 secretion [1], muab kev sib txuas ntawm o, lysosome cia, thiab autophagy impairment, peb cov txheej txheem loj uas muaj feem cuam tshuam rau -syn clearance thiab PD pathogenesis. Kev ua haujlwm ntau ntxiv yog xav tau los piav qhia qhov cuam tshuam ntawm cov kev hloov pauv hauv lub cev tiv thaiv kab mob hauv cov txheej txheem-syn neurodegenerative. Yog xav nyeem ntxiv mus saib: [126, 163].

Cov lus xaus

Nws yog qhov tseeb ntxiv tias lub cev tiv thaiv kab mob yog ib qho tseem ceeb ntawm cov kab mob pathogenesis hauv PD, vim tias muaj cov pov thawj muaj zog rau kev tiv thaiv kab mob hauv lub cev thiab yoog raws hauv tib neeg cov kab mob thiab -syn raws li tsiaj cov qauv. Raws li kev tshawb fawb tau nce zuj zus thiab cov txheej txheem rau kev tshawb nrhiav tau hloov zuj zus, nws pom tseeb tias cov kev hloov pauv hauv lub cev tiv thaiv kab mob hauv PD tshwm sim ntxov thiab hloov pauv hloov pauv nrog kev kis kab mob. Txawm hais tias yav dhau los xav tias yuav koom nrog CNS-kev tiv thaiv kab mob tshwj xeeb, kev tshawb fawb tam sim no tau pom tias ob lub hlwb, nrog rau cov kab mob hauv nruab nrog cev, tau koom nrog hauv qhov kev tshwm sim inflammatory no muab pov thawj muaj zog rau innate thiab adaptive immune system crosstalk hauv CNS thiab periphery.

Ntawm qhov tseem ceeb ntawm cov kab mob pathogenesis, -syn tau ua pov thawj tias nws yog ib qho tseem ceeb vim nws tsis tsuas yog pab txhawb rau cov kab mob pathology pom hauv PD postmortem cov ntaub so ntswg tab sis tseem yog qhov tseem ceeb hauv kev ua kom muaj zog thiab ua rau mob thiab neurodegeneration hauv tib neeg PD. Cov hauv nruab nrab txoj hauv kev ntawm -syn-tsav innate thiab yoog lub cev tiv thaiv kab mob tau tsis ntev los no tau txiav tawm hauv-syn-raws li tsiaj cov qauv, uas tau ua haujlwm hauv kev ua qauv rau tib neeg tus kab mob. Siv cov qauv tsiaj no ua ke nrog tib neeg cov kev tshawb fawb tau tso cai rau peb txheeb xyuas txoj hauv kev tshiab uas muaj peev xwm tsav cov kab mob neurodegeneration hauv PNS thiab CNS uas tsis yog tsuas yog lub cev tiv thaiv kab mob xwb, tab sis kuj cuam tshuam rau lub plab microbiome, genetic predisposition, thiab ib puag ncig tiv thaiv kab mob. Peb ntseeg hais tias kev soj ntsuam ntawm qhov ntev ntawm cov kev hloov pauv hauv cov kab mob inflammatory hauv cov neeg mob, ua ke nrog peripheral immune profileing, kuaj plab microbiome, -syn ntshav thiab CSF tsom xam, thiab PET imaging tej zaum yuav muab lub sijhawm tshwj xeeb rau kev tshawb nrhiav lossis kev tshawb pom ntawm lub cev tsis muaj zog. biomarkers los kwv yees kab mob tshwm sim thiab kev loj hlob. Kev tshawb pom ntxov thiab kev nkag siab meej txog kev tiv thaiv kab mob hauv PD tuaj yeem ua rau cov tshuaj kho tshiab uas tsis yog tsom rau CNS cov khoom tshwj xeeb nkaus xwb tab sis tseem tsom mus rau qhov chaw, muab kev tiv thaiv kab mob thiab tiv thaiv kab mob.

Kev lees paub

Peb ua tsaug rau Prof Dr. Malú Tansey rau nws txoj kev cob qhia, thiab muab nqi zog thiab kev pom zoo txog kev sib tham txog kev tsom mus rau qhov kev tshuaj xyuas no.

Nyiaj txiag

Cov kws sau ntawv tshaj tawm tsis muaj kev sib cav txog kev txaus siab. Cov nyiaj pab txhawb rau cov kev tshawb fawb hauv kab lus no yog muab los ntawm Michael J. Fox Foundation, Danish Parkinson Foundation, thiab Aarhus University Forskningsfond AU IDEAS Center NEURODIN. SAF tau txais nyiaj los ntawm Ph.D. kev sib raug zoo los ntawm Ph.D. Tsev kawm ntawv ntawm Health Kws qhia ntawv, Aarhus University.

Qhib Access

Kab lus no tau tso cai raws li Creative Commons Attribution 4.0 Daim ntawv tso cai thoob ntiaj teb, uas tso cai siv, sib koom, hloov kho, faib, thiab luam tawm hauv ib qho nruab nrab lossis hom ntawv, tsuav yog koj muab credit rau tus thawj sau ) thiab qhov chaw, muab qhov txuas mus rau Creative Commons daim ntawv tso cai, thiab qhia seb puas tau hloov pauv. Cov duab lossis lwm yam khoom siv thib peb hauv tsab xov xwm no suav nrog hauv tsab xov xwm Creative Commons daim ntawv tso cai tshwj tsis yog tau qhia lwm yam hauv kab qiv nyiaj rau cov khoom siv. Yog tias cov ntaub ntawv tsis suav nrog hauv tsab xov xwm Creative Commons daim ntawv tso cai thiab koj qhov kev npaj siv tsis raug tso cai los ntawm txoj cai lij choj lossis tshaj qhov kev tso cai siv, koj yuav tsum tau txais kev tso cai ncaj qha los ntawm tus tuav ntaub ntawv.

Cov ntaub ntawv

1. Afaki E, Moaven N, Borger DK, Lopez G, Westbroek W, Chae JJ et al (2016) Lysosomal cia thiab impaired autophagy ua rau inflammasome activation hauv Gaucher macrophages. Hnub nyoog Cell 15:77–88. https://doi.org/10.1111/acel.12409

2. Ahmadi Rastegar D, Ho N, Halliday GM, Dzamko N (2019) Parkinson qhov kev nce qib kev kwv yees siv tshuab kev kawm thiab cov ntshav cytokines. NPJ Parkinson Dis 5:14. https://doi. org/10.1038/s41531-019-0086-4

3. Akhtar RS, Licata JP, Luk KC, Shaw LM, Trojanowski JQ, Lee VM (2018) Kev ntsuas ntawm auto-antibodies rau alpha-synuclein hauv cov ntshav thiab cerebral spinal fluid ntawm cov neeg mob Parkinson's disease. J Neurochem 145:489–503. https://doi. org/10.1111/jnc.14330

4. Al-Qassabi A, Tsao TS, Racolta A, Kremer T, Canamero M, Belousov A, et al (2020) Immunohistochemical detection of synuclein pathology nyob rau hauv daim tawv nqaij nyob rau hauv idiopathic ceev lub qhov muag txav cwj pwm pw tsaug zog thiab Parkinsonism. Mov Disord. https://doi. org/10.1002/mds.28399

5. Anthony IC, Crawford DH, Bell JE (2003) B lymphocytes nyob rau hauv lub hlwb ib txwm: sib piv nrog HIV-koom nrog lymphoid infiltrates thiab lymphomas. Paj Lug 126:1058–1067. https://doi.org/10.1093/ brain/awg118

6. Atashrazm F, Hammond D, Perera G, Dobson-Stone C, Mueller N, Pickford R et al (2018) Txo cov kev ua haujlwm ntawm glucocerebrosidase hauv monocytes los ntawm cov neeg mob Parkinson's disease. Phau Ntawv Nkauj 8:15446. https://doi.org/10.1038/s41598-018-33921-x

7. Aufray C, Fogg D, Garfa M, Elain G, Koom-Lambert O, Kayal S, et al (2007) Kev soj ntsuam cov hlab ntsha thiab cov ntaub so ntswg los ntawm cov pej xeem ntawm monocytes nrog kev saib xyuas tus cwj pwm. Sci (New York, NY) 317:666–670. https://doi.org/10.1126/science.1142883

8. Bae EJ, Lee HJ, Rockenstein E, Ho DH, Park EB, Yang NY, et al (2012) Antibody-aided clearance of extracellular alpha-synuclein inhibits cell-to-cell aggregate transmissions. J Neurosci 32: 13454–13469. https://doi.org/10.1523/JNEUR OSCI.{11}}.2012

9. Barkholt P, Sanchez-Guajardo V, Kirik D, Romero-Ramos M (2012) Lub sij hawm ntev polarization ntawm microglia raws li alpha-synuclein overexpression nyob rau hauv nonhuman primates. Neuroscience. https://doi. org/10.1016/j.neuroscience.2012.02.004

1 0. Besong-Agbo D, Hma E, Jessen F, Oechsner M, Hametner E, Poewe W et al (2013) Ib txwm tshwm sim alpha-synuclein autoantibody qib qis dua hauv cov neeg mob Parkinson's disease. Neurology 80: 169–175. https://doi.org/10.1212/WNL.0b013 e31827b90d1

11. Biber K, Neumann H, Inoue K, Boddeke HW (2007) Neuronal "On" thiab "Off" signals tswj microglia. Trends Neurosci 30: 596–602. https://doi.org/10.1016/j.tins.2007.08.007

12. Bliederhaeuser C, Grozdanov V, Speidel A, Zondler L, Ruf WP, Bayer H, et al (2016) Hnub nyoog-dependent defects ntawm alpha-synuclein oligomer uptake hauv microglia thiab monocytes. Acta Neuropathol 131: 379–391. https://doi.org/10.1007/s00401-015-1504-2

13. Blum-Degen D, Muller T, Kuhn W, Gerlach M, Przuntek H, Riederer P (1995) Interleukin -1 beta thiab interleukin-6 tau nce siab hauv cov kua dej cerebrospinal ntawm Alzheimer's thiab de novo Parkinson's cov neeg mob. Neurosci Lett 202:17–20

14. Bohnen NI, Hu MTM (2019) Pw tsaug zog cuam tshuam raws li kev pheej hmoo thiab kev loj hlob ntawm tus kab mob Parkinson. J Parkinsons Dis 9:603–614. https://doi.org/10.3233/jpd-191627

15. Borghammer P, Van Den Berge N (2019) Brain-first versus gutfrst Parkinson's disease: a hypothesis. J Parkinsons Dis 9:S281–S295. https://doi.org/10.3233/JPD-191721

16. Brochard V, Combadiere B, Prigent A, Laouar Y, Perrin A, Beray-Berthat V et al (2009) Infiltration of CD4 plus lymphocytes into the brain contributes to neurodegeneration in a mouse model of Parkinson's disease. J Clin Invest 119:182–192. https://doi. org/10.1172/JCI36470 (36470[pii])

17. Brockmann K, Schulte C, Schneiderhan-Marra N, Apel A, PontSunyer C, Vilas D et al (2017) Inflammatory profile discriminates clinical subtypes in LRRK2-associated Parkinson's disease. Eur J Neurol 24:427-e426. https://doi.org/10.1111/ene.13223

18. Brudek T (2019) Kab mob plab hnyuv thiab Parkinson's disease. J Parkinsons Dis 9:S331–S344. https://doi.org/10.3233/ JPD-191729

19. Brudek T, Winge K, Folke J, Christensen S, Fog K, Pakkenberg B et al (2017) Autoimmune antibody poob rau Parkinson tus kab mob thiab ntau yam kab mob atrophy; ib kauj ruam mus rau immunotherapeutic tswv yim. Mol Neurodegener 12:44. https://doi. org/10.1186/s13024-017-0187-7

20. Burbulla LF, Jeon S, Zheng J, Song P, Silverman RB, Krainc D (2019) Ib qho modulator ntawm hom tsiaj qus glucocerebrosidase txhim kho cov kab mob phenotypes hauv dopaminergic neuronal qauv ntawm Parkinson tus kab mob. Sci Transl Med. https://doi.org/10.1126/scitr assumed.aau6870

21. Bussi C, Peralta Ramos JM, Arroyo DS, Gallea JI, Ronchi P, Kolovou A, et al (2018) Alpha-synuclein fibrils recruit TBK1 thiab OPTN rau lysosomal puas qhov chaw thiab induce autophagy hauv microglial hlwb. J Cell Sci. https://doi.org/10.1242/jcs.226241

22. Cabezudo D, Baekelandt V, Lobbestael E (2020) Ntau qhov kev xav ntawm tus kab mob Parkinson: LRRK2 thiab mob. Pem Hauv Ntej Neurosci 14: 376. https://doi.org/10.3389/fnins.2020.00376

23. Cao S, Standaert DG, Harms AS (2012) Lub gamma saw subunit ntawm Fc receptors yog yuav tsum tau rau alpha-synuclein-induced proinflammatory signaling nyob rau hauv microglia. J Neuroinflammation 9:259.https://doi.org/10.1186/1742-2094-9-259

24. Cao S, Theodore S, Standaert DG (2010) Fcgamma receptors yog xav tau rau NF-kappaB signaling, microglial activation, thiab dopaminergic neurodegeneration hauv AAV-synuclein nas qauv ntawm Parkinson tus kab mob. Mol Neurodegener 5:42. https://doi.org/10.1186/1750-1326-5-42

25. Cebrian C, Zucca FA, Mauri P, Steinbeck JA, Studer L, Scherzer CR, et al (2014) MHC-I qhia renders catecholaminergic neurons susceptible to T-cell-mediated degeneration. Xwm Txheej Taug Kev 5:3633.

26. Chahine LM, Beach TG, Brumm MC, Adler CH, Coffey CS, Mosovsky S, et al (2020) Hauv vivo faib alpha-synuclein hauv ntau cov ntaub so ntswg thiab biofluids hauv Parkinson tus kab mob. Neurology 95:e1267–e1284. https://doi.org/10.1212/WNL.0000000000 010404

27. Chahine LM, Qiang J, Ashbridge E, Minger J, Yearout D, Horn S, et al (2013) Clinical and biochemical sib txawv ntawm cov neeg mob Parkinson's disease with vs without GBA mutations. JAMA Neurol 70:852–858. https://doi.org/10.1001/jamaneurol .2013.1274

28. Challis C, Hori A, Sampson TR, Yoo BB, Challis RC, Hamilton AM et al (2020) Gut-seeded alpha-synuclein fibrils txhawb lub plab dysfunction thiab hlwb pathology tshwj xeeb hauv cov nas laus. Nat Neurosci 23:327–336. https://doi.org/10.1038/s4159 3-020-0589-7

29. Chatterjee K, Roy A, Banerjee R, Choudhury S, Mondal B, Halder S, et al (2020) Inflammasome thiab alpha-synuclein nyob rau hauv tus kab mob Parkinson: txoj kev kawm hla ntu. J Neuroimmunol 338:577089. https://doi.org/10.1016/j.jneuroim.2019.577089

30. Chavan SS, Tracey KJ (2017) Qhov tseem ceeb neuroscience hauv kev tiv thaiv kab mob. J Immunol 198:3389–3397. https://doi.org/10.4049/ Immunol.1601613

31. Chen Z, Li G, Liu J (2020) Autonomic dysfunction in Parkinson's disease: Implications for pathophysiology, Diagnosis, and treatment. Neurobiol Dis 134:104700. https://doi.org/10.1016/j. nbd.2019.104700

32. Choi YR, Kang SJ, Kim JM, Lee SJ, Jou I, Joe EH et al (2015) FcgammaRIIB mediates the inhibitory effect of aggregated alpha-synuclein on microglial phagocytosis. Neurobiol Dis 83:90–99. https://doi.org/10.1016/j.nbd.2015.08.025

33. Christiansen JR, Olesen MN, Otzen DE, Romero-Ramos M, Sanchez-Guajardo V (2016) tshuaj tiv thaiv alpha-Synuclein modulates regulatory T cell activation thiab microglia nyob rau hauv tsis muaj hlwb pathology. J Neuroinflamation 13:74. https://doi.org/10.1186/s12974-016-0532-8

34. Codolo G, Plotegher N, Pozzobon T, Brucale M, Tessari I, Bubacco L, et al (2013) Ua rau tus mob inflammasome los ntawm aggregated alpha-synuclein, ib qho inflammatory teb nyob rau hauv synucleinopathies. ib 8:e55375. https://doi.org/10.1371/journ al.pone.0055375 ib

35. Croisier E, Moran LB, Dexter DT, Pearce RK, Graeber MB (2005) Microglial inflammatory in the Parkinsonian substantia nigra: relationship to alpha-synuclein deposition. J Neuroinflamation 2:14

36. Cullen V, Sardi SP, Ng J, Xu YH, Sun Y, Tomlinson JJ et al (2011) Acid beta-glucosidase mutants linked to Gaucher disease, Parkinson disease, thiab Lewy body dementia alter alpha-synuclein processing. Ann Neurol 69:940–953. https://doi. org/10.1002/ana.22400

37. Daher JP (2017) Kev sib cuam tshuam ntawm LRRK2 thiab alpha-synuclein hauv Parkinson tus kab mob. Adv Neurobiol 14:209–226. https://doi. org/10.1007/978-3-319-49969-7_11

38. Daniele SG, Beraud D, Davenport C, Cheng K, Yin H, Maguire-Zeiss KA (2015) Ua kom MyD88- nyob ntawm TLR1/2 signaling los ntawm misfolded alpha-synuclein, protein txuas rau neurodegenerative mob. Ntawv Nkauj 8:ra45. https://doi. org/10.1126/scisignal.2005965

39. Dhillon JS, Trejo-Lopez JA, Rife C, Levites Y, Sacino AN, Borchelt DR, et al (2019) Kev sib piv kev soj ntsuam ntawm in vivo induction thiab kis ntawm alpha-synuclein pathology hauv cov nas transgenic los ntawm MSA hlwb lysate thiab recombinant alpha-synuclein fibrils. Acta Neuropathol Commun 7:80. https://doi. org/10.1186/s40478-019-0733-3

40. Doorn KJ, Moors T, Drukarch B, van de Berg W, Lucassen PJ, van Dam AM (2014) Microglial phenotypes and call-like receptor 2 in the substantia nigra and hippocampus of incidental Lewy body disease case and Parkinson's disease. Acta Neuropathol Commun 2:90. https://doi. org/10.1186/s40478-014-0090-1

41. Drouin-Ouellet J, St-Amour I, Saint-Pierre M, LamontagneProulx J, Kriz J, et al (2015) Tus xov tooj hu zoo li receptor qhia hauv cov ntshav thiab hlwb ntawm cov neeg mob thiab tus nas qauv ntawm tus kab mob Parkinson. Int J Neuropsychopharmacol. https://doi.org/10.1093/ ijnp/pyu103

42. Dufy MF, Collier TJ, Patterson JR, Kemp CJ, Luk KC, Tansey MG, et al (2018) Lewy body-like alpha-synuclein inclusions trigger reactive microgliosis before nigral degeneration. J Neuroinflamation 15:129. https://doi.org/10.1186/s1297 4-018-1171-z

43. Dzamko N, Rowe DB, Halliday GM (2016) Nce peripheral o nyob rau hauv asymptomatic leucine-nplua nuj rov kinase 2 mutation carriers. Mov Disord 31: 889–897. https://doi.org/10.1002/ mds.26529

44. Earls RH, Menees KB, Chung J, Barber J, Gutekunst CA, Hazim MG, et al (2019) Intrastriatal txhaj ntawm preformed alpha-synuclein fibrils alters central thiab peripheral immune cell profiles nyob rau hauv cov nas uas tsis yog-transgenic. J Neuroinflamation 16:250. https://doi. org/10.1186/s12974-019-1636-8

45. Earls RH, Menees KB, Chung J, Gutekunst CA, Lee HJ, Hazim MG, Rada B, Wood LB, Lee JK (2020) NK hlwb tshem tawm alpha-synuclein thiab depletion ntawm NK hlwb exacerbates synuclein pathology hauv tus qauv nas. ntawm alpha-synucleinopathy. Proc Natl Acad Sci USA 117:1762–1771. https://doi.org/10.1073/ pnas.1909110117

46. ​​Edison P, Ahmed I, Fan Z, Hinz R, Gelosa G, Ray Chaudhuri K, et al (2013) Microglia, amyloid, thiab qabzib metabolism hauv Parkinson tus kab mob nrog thiab tsis muaj dementia. Neuropsychopharmacology 38: 938–949. https://doi.org/10.1038/npp.2012.255

47. El-Agnaf O, Overk C, Rockenstein E, Mante M, Florio J, Adam A, et al (2017) Kev sib txawv ntawm kev siv tshuaj tiv thaiv kab mob nrog cov tshuaj tiv thaiv tsom rau alpha-synuclein oligomers thiab fibrils nyob rau hauv ib tug transgenic qauv ntawm synucleinopathy. Neurobiol Dis 104:85–96. https://doi.org/10.1016/j.nbd.2017.05.002

48. Emmer KL, Waxman EA, Covy JP, Giasson BI (2011) E46K human alpha-synuclein transgenic nas tsim Lewy-zoo li thiab tau pathology txuam nrog hnub nyoog-dependent, detrimental motor impairment. J Biol Chem 286:35104–35118. https://doi. org/10.1074/jbc.M111.247965 (M111.247965[pii])

49. Ntxuam Z, Pan YT, Zhang ZY, Yang H, Yu SY, Zheng Y et al (2020) Kev ua kom lub cev ntawm NLRP3 inflammasome thiab plasma alpha-synuclein theem muaj feem cuam tshuam nrog lub cev muaj zog thiab kev loj hlob ntawm tus kab mob Parkinson. J Neuroinflamation 17:11. https://doi.org/10.1186/s12974-019-1670-6

50. Fellner L, Irschick R, Schanda K, Reindl M, Klimaschewski L, Poewe W et al (2013) Tus xov tooj zoo li 4 yog xav tau rau alpha-synuclein nyob ntawm kev ua kom microglia thiab astroglia. Chiv Keeb 61:349–360. https://doi.org/10.1002/glia.22437

51. Ferreira SA, Romero-Ramos M (2018) Microglia teb thaum tus kab mob Parkinson: alpha-synuclein cuam tshuam. Pem Hauv Ntej Cell Neurosci 12: 247. https://doi.org/10.3389/fncel.2018.00247

52. Filippini A, Gennarelli M, Russo I (2019) Alpha-synuclein thiab glia nyob rau hauv Parkinson tus kab mob: muaj txiaj ntsig los yog kev puas tsuaj rau cov kab mob endo-lysosomal? Cell Mol Neurobiol 39:161–168.https://doi.org/10.1007/s10571-019-00649-9

53. Freeman D, Cedillos R, Choyke S, Lukic Z, McGuire K, Marvin S et al (2013) Alpha-synuclein induces lysosomal rupture thiab cathepsin-dependent reactive oxygen species after endocytosis. ib 8:e62143. https://doi.org/10.1371/journ al.pone.0062143 ib

54. Funk N, Wieghofer P, Grimm S, Schaefer R, Buhring HJ, Gasser T et al (2013) Characterization of peripheral hematopoietic stem cells and monocytes in Parkinson's disease. Mov Disord 28:392–395. https://doi.org/10.1002/mds.25300

55. Gao HM, Kotzbauer PT, Uryu K, Leight S, Trojanowski JQ, Lee VM (2008) Neuroinflammation and oxidation/nitration of alpha-synuclein linked to dopaminergic neurodegeneration. J Neurosci 28:7687–7698. https://doi.org/10.1523/JNEUROSCI.0143- 07.2008 (28/30/7687[pii])

56. Gao HM, Zhang F, Zhou H, Kam W, Wilson B, Hong JS (2011) Neuroinflammation and alpha-synuclein dysfunction potentiate each other, drive the chronic progression of neurodegeneration in a mouse model of Parkinson's disease. Environ Health Perspect 119:807–814. https://doi.org/10.1289/ehp.1003013

57. Gardai SJ, Mao W, Schule B, Babcock M, Schoebel S, Lorenzana C, et al (2013) Elevated alpha-synuclein impairs innate immune cell function thiab muab lub peev xwm peripheral biomarker rau Parkinson tus kab mob. ib 8:e71634. https://doi.org/10.1371/journal.pone.0071634

58. Gardet A, Benita Y, Li C, Sands BE, Ballester I, Stevens C et al (2010) LRRK2 yog koom nrog IFN-gamma teb thiab tus tswv teb rau cov kab mob. J Immunol 185:5577–5585. https://doi. org/10.4049/Immunol.1000548

59. Garretti F, Agalliu D, Lindestam Arlehamn CS, Sette A, Sulzer D (2019) Autoimmunity in Parkinson's disease: lub luag hauj lwm ntawm alphasynuclein-specifc T hlwb. Pem Hauv Ntej Immunol 10:303. https://doi. org/10.3389/fmmu.2019.00303

60. George S, Rey NL, Tyson T, Esquibel C, Meyerdirk L, Schulz E, et al (2019) Microglia cuam tshuam alpha-synuclein cell-to-cell hloov hauv tus nas qauv ntawm tus kab mob Parkinson. Phau Ntawv Nkauj 14:34. https://doi.org/10.1186/s13024-019-0335-3

61. Gerhard A, Pavese N, Hotton G, Turkheimer F, Es M, Hammers A, et al (2006) Hauv vivo imaging of microglial activation with [11C] (R)-PK11195 PET in idiopathic Parkinson's disease. Neurobiol Dis 21:404–412. https://doi.org/10.1016/j.nbd.2005.08.002

62. Giasson BI, Duda JE, Quinn SM, Zhang B, Trojanowski JQ, Lee VM (2002) Neuronal alpha-synucleinopathy nrog mob hnyav txav hauv nas qhia A53T tib neeg alpha-synuclein. Neuron 34:521–533

63. Gliem M, Schwaninger M, Jander S (2016) Tiv thaiv cov yam ntxwv ntawm peripheral monocytes / macrophages hauv mob stroke. Biochim Biophys Acta 1862: 329–338. https://doi.org/10.1016/j.bbadi s.2015.11.004

64. Gomez-Isla T, Irizarry MC, Mariash A, Cheung B, Soto O, Schrump S et al (2003) Lub cev muaj zog thiab gliosis nrog cov cim dopaminergic khaws cia hauv tib neeg alpha-synuclein A30P transgenic nas. Neurobiol Hnub nyoog 24: 245–258

65. Gordon R, Albornoz EA, Christie DC, Langley MR, Kumar V, Mantovani S et al (2018) Inflammasome inhibition tiv thaiv alpha-synuclein pathology thiab dopaminergic neurodegeneration hauv nas. Sci Transl Med. https://doi.org/10.1126/scitranslm ed.aah4066

66. Grey MT, Munoz DG, Grey DA, Schlossmacher MG, Woulfe JM (2014) Alpha-synuclein nyob rau hauv appendiceal mucosa ntawm neurologically intact subjects. Mov Disord 29:991–998. https://doi. org/10.1002/mds.25779

67. Grozdanov V, Bliederhaeuser C, Ruf WP, Roth V, FundelClemens K et al (2014) Inflammatory dysregulation of blood monocytes in Parkinson's disease. Acta Neuropathol 128: 651–663. https://doi.org/10.1007/s00401-014-1345-4

68. Grozdanov V, Bousset L, Hofmeister M, Bliederhaeuser C, Meier C, Madiona K et al (2019) Ua kom muaj zog tiv thaiv kab mob los ntawm pathologic alpha-synuclein hauv Parkinson tus kab mob. Ann Neurol 86: 593–606. https://doi.org/10.1002/ana.25557

69. Gundner AL, Duran-Pacheco G, Zimmermann S, Ruf I, Moors T, Baumann K et al (2019) Path mediation analysis qhia GBA cuam tshuam rau Lewy lub cev kab mob los ntawm kev nce qib alpha-synuclein. Neurobiol Dis 121:205–213. https://doi.org/10.1016/j. nbd.2018.09.015

70. Guo M, Wang J, Zhao Y, Feng Y, Han S, Dong Q et al (2020) Microglial exosomes pab txhawb kev sib kis ntawm alpha-synuclein hauv Parkinson tus kab mob. Lub hlwb. https://doi.org/10.1093/brain/awaa0 90

71. Gustafsson G, Eriksson F, Moller C, da Fonseca TL, Outeiro TF, Lannfelt L et al (2017) Cellular uptake of alpha-synuclein oligomer-selective antibodies is enhanced by the extracellular muaj nyob ntawm alpha-synuclein thiab mediated ntawm Fonderella. cov receptors. Cell Mol Neurobiol 37:121–131. https://doi.org/10.1007/ s{10}}

72. Gustot A, Gallea JI, Sarroukh R, Celej MS, Ruysschaert JM, Raussens V (2015) Amyloid fibrils yog cov tshuaj molecular ua rau mob ntawm tus kab mob Parkinson. Biochem J 471: 323–333.https://doi.org/10.1042/BJ20150617

73. Hall S, Janelidze S, Surova Y, Widner H, Zetterberg H, Hansson O (2018) Cerebrospinal fluid concentrations of inflammatory markers in Parkinson's disease thiab atypical parkinsonian disorders. Phau Ntawv Nkauj 8:13276. https://doi.org/10.1038/s41598-018- 31517-z

74. Halliday GM, Stevens CH (2011) Glia: cov thawj coj thiab cov thawj coj ntawm cov kab mob hauv Parkinson's disease. Mov Disord 26:6–17. https://doi.org/10.1002/mds.23455 ib

75. Hamza TH, Zabetian CP, Tenesa A, Laederach A, Montimurro J, Yearout D et al (2010) Kev hloov pauv caj ces feem ntau hauv cheeb tsam HLA yog txuam nrog cov kab mob Parkinson tus kab mob lig. Nat Genet 42:781–785. https://doi.org/10.1038/ng.642

76. Hansson O, Hall S, Ohrfelt A, Zetterberg H, Blennow K, Minthon L et al (2014) Qib ntawm cov kua dej cerebrospinal alpha-synuclein oligomers tau nce hauv Parkinson tus kab mob nrog dementia thiab dementia nrog Lewy lub cev piv rau Alzheimer's disease. Alzheimer's Res Ther 6:25. https://doi.org/10.1186/alzrt 255 ib

77. Harms AS, Cao S, Rowse AL, Thome AD, Li X, Mangieri LR, et al (2013) MHCII yog xav tau rau alpha-synuclein-induced activation ntawm microglia, CD4 T cell proliferation, thiab dopaminergic neurodegeneration. J Neurosci 33: 9592–9600. https://doi. org/10.1523/JNEUROSCI.5610-12.2013

78. Harms AS, Delic V, Thome AD, Bryant N, Liu Z, Chandra S, et al (2017) alpha-Synuclein fibrils recruit peripheral immune cells nyob rau hauv nas hlwb ua ntej neurodegeneration. Acta Neuropathol Commun 5:85. https://doi.org/10.1186/s40478-017-0494-9

79. Harms AS, Standaert DG (2014) Monocytes thiab Parkinson's disease: invaders los ntawm sab nraud? Mov Disord 29:1242. https://doi.org/10.1002/mds.25993

80. Harms AS, Thome AD, Yan Z, Schonhof AM, Williams GP, Li X et al (2018) Peripheral monocyte nkag yog yuav tsum tau rau alpha-synuclein-induced o thiab Neurodegeneration nyob rau hauv ib tug qauv ntawm Parkinson tus kab mob. Exp Neurol 300: 179–187. https://doi.org/10.1016/j.expneurol.2017.11.010

81. Heintz-Buschart A, Pandey U, Wicke T, Sixel-Doring F, Janzen A, Sittig-Wiegand E et al (2018) Qhov ntswg thiab plab microbiome nyob rau hauv Parkinson tus kab mob thiab idiopathic ceev qhov muag txav kev coj cwj pwm tsis zoo. Mov Disord 33:88–98. https://doi. org/10.1002/mds.27105

82. Ho PW, Leung CT, Liu H, Pang SY, Lam CS, Xian J, et al (2020) Age-dependent accumulation of oligomeric SNCA/alpha-synuclein from impaired degradation in mutant LRRK2 knock-in mouse model of Parkinson disease : lub luag hauj lwm rau kev kho mob ua kom cov chaperone-mediated autophagy (CMA). Phau Ntawv Nkauj 16:347–370.

For more information:1950477648nn@gmail.com