Autophagy-Lysosomal Pathway Raws li Lub Hom Phiaj Kho Mob hauv Parkinson's Disease

Thov hu rauoscar.xiao@wecistanche.comyog xav paub ntxiv

Abstract:Cellular zoo tswj systems tau txais kev saib xyuas ntau nyob rau hauv kaum xyoo tsis ntev los no. Ntawm cov no, autophagy yog ib qho kev tiv thaiv tus kheej uas tsis tu ncua tshem tawm cov tshuaj lom ntawm tes thiab ua raws li kev tiv thaiv kev laus. Nws yog ib qho tseem ceeb rau kev ciaj sia ntawm tes thiab khaws cia homeostasis. Ob peb lub xovtooj ntawm tes-hom-dependent canonical lossis non-canonical autophagy txoj hauv kev tau tshaj tawm qhia qhov sib txawv ntawm cov kev xaiv uas hais txog cov substrates tsom. Ntawm no, peb muab kev tshuaj xyuas tshiab ntawm cov tshuab autophagy thiab sib tham txog lub luag haujlwm ntawm ntau hom autophagy hauv cov kab mob neurodegenerative, nrog rau kev tsom mus rau Parkinson's disease. Peb piav qhia txog qhov kev tshawb pom tsis ntev los no uas tau ua rau muaj kev pom zoo ntawm cov tswv yim kho mob tsom mus rau autophagy los hloov cov kev hloov pauv ntawm Parkinson tus kab mob.

Ntsiab lus:autophagy; lysosomes; kab mob neurodegenerative; Tus kab mob Parkinson; autoimmunity

Thov nias ntawm no kom paub ntxiv

1. Taw qhia

Txawm hais tias qee lub ntsiab lus ntawm Parkinson's disease (PD) tau piav qhia ntev dhau los, thawj qhov kev piav qhia meej ntawm tus kab mob no tau luam tawm xyoo 1817 los ntawm James Parkinson [1]. Txij thaum ntawd los, kev siv zog ntau heev tau ua kom nkag siab txog lub hauv paus pathogenesis thiab cov kab mob pathological ntawm cov kab mob nyuaj no, hais txog kev hloov pauv neuropathological thiab anatomopathological [2-5]. PD yog ib hom kab mob ntau yam uas muaj ntau yam ua rau muaj kev cuam tshuam, suav nrog cov noob caj noob ces, ib puag ncig, molecular, thiab cellular Cheebtsam. PD yog tus cwj pwm los ntawm qhov dav dav ntawm lub cev muaj zog thiab tsis yog lub cev muaj zog thiab cov tsos mob. Lawv suav nrog kev so tremor, bradykinesia, postural instability / unsteady gait, thiab rigidity, nrog rau kev puas siab puas ntsws, pw tsaug zog, dysautonomic disorders, mob, anosmia, thiab kev txawj ntse teeb meem. Lub cev muaj zog cov cim tshwm sim feem ntau los ntawm kev poob ntawm dopaminergic (DA) neurons nyob rau hauv substantia nigra pars compacta (SNpc) thiab intracellular inclusions ntawm aggregated thiab misfolded -synuclein (c-syn), encapsulated los yog tsis nyob rau hauv Lewy lub cev (LB) thiab Lewy neurites ( LN) hauv cov neurons[3,6](Daim duab 1; saib cov ntawv ntxiv rau cov ntsiab lus).

Cov tsos mob ntawm PD pib maj mam nrog hnub nyoog.dab tsi yog cistancheLawv tuaj yeem pib nrog kev tshee me ntsis ntawm ib txhais tes thiab kev xav ntawm qhov tawv nqaij ntawm lub cev; bradykinesia yog nquag. Cov kev tshawb fawb tsis ntev los no tau lees paub tias ntau dua 3 feem pua ​​​​ntawm cov pej xeem ntawm cov hnub nyoog 65 xyoo raug cuam tshuam los ntawm PD. Hauv 5 feem pua ​​-10 feem pua ​​​​ntawm cov neeg mob, txawm li cas los xij, cov tsos mob ntawm PD tshwm ua ntej; qhov no yog hu ua Young-onset PD (YOPD). Cov txiv neej muaj 50 feem pua ​​​​yuav tsim PD dua li cov poj niam, tab sis qhov kev pheej hmoo rau cov poj niam zoo li muaj hnub nyoog.

Daim duab 1. Kev tshawb pom Neuropathological hauv Parkinson tus kab mob. (A, B) Post-mortem mesencephalon thiab pons los ntawm tus neeg mob tswj (A) thiab los ntawm tus neeg mob nrog PD (B): SN tshwm sim paler hauv B vim dopaminergic denervation. (C), SN, H&E staining (× 250).(D): H&E staining (× 250) ntawm LB hauv cortical neuron. Lub xub dub qhia tau tias LB. Cov ntawv luv luv tsis tau piav qhia hauv cov ntawv nyeem: H&E, hematoxylin, thiab eosin.

Lub hauv paus ua rau PD tseem tsis paub ntau.bioflavonoidsQee qhov xwm txheej ntawm PD tau txuas nrog kev hloov pauv caj ces, tab sis qhov tseeb ntawm keeb kwm ntawm tus kab mob no nyuaj rau tsim. Tseeb tiag, tsuas yog 15 feem pua ​​​​ntawm cov neeg mob PD muaj keeb kwm ntawm tsev neeg ntawm tus kab mob. Qee cov noob tau cuam tshuam nrog cov kab mob sib txawv, raug, lossis tsis tshua muaj cov kab mob, uas suav nrog cov menyuam yaus lossis cov neeg laus pib, ntxov lossis lig, autosomal recessive, dominant, lossis X-txuas cov ntawv [4,7-9]. Cov kev pheej hmoo ua rau muaj feem cuam tshuam nrog qee pawg haiv neeg kuj raug txheeb xyuas. Cov noob feem ntau txuas rau PD suav nrog GBA, LRRK2, PRKN, SNCA, ATP13A2, ATP10B, DI-1,DNAIC6, FBXO7,HTRA2,MAPT, PINK1,PLA2G6,VPS35, thiab VPS13C[4,{19} }]. Feem ntau ntawm cov noob no encode cov proteins uas txuas ncaj qha lossis tsis ncaj qha rau cov txheej txheem tswj kom zoo uas yog qhov tseem ceeb hauv kev tswj hwm cell homeostasis, vesicular transport pathways, autophagy processes, thiab endo-lysosomal system. Lwm yam kev hloov pauv caj ces kuj tau cuam tshuam nrog PD, suav nrog kev hloov pauv hauv cov noob caj noob ces, xws li DNA methylation, chromatin remodeling, histone modifications, microRNAs, thiab ntev tsis-coding RNAs [4,14].

2. Pathogenesis thiab Pathology

Cov kev tshawb fawb Clinicopathological qhia txog qhov qeeb qeeb ntawm PD los ntawm thaj tsam ventrolateral ntawm SNpc, tom qab ntawd kis mus rau lwm thaj chaw hauv hlwb [15]. Cov tsos mob ntawm PD tuaj yeem pom tau thaum lub degeneration ntawm DA neurons nce hauv SNpc. LBs raug pom ntawm qhov chaw ntawm kev puas tsuaj neuronal (Daim duab 1). Nyob rau hauv ib txwm physiology, -syn tso rau hauv cov qauv no ua haujlwm hauv nruab nrab hauv endocytosis; kev lag luam vesicle; synthesis, cia, thiab tso tawm ntawm dopamine; Ca2 ntxiv rau homeostasis; microtubule dynamics; thiab lwm yam txheej txheem [16]. Yog li, kev ua haujlwm neuronal yog nyob ntawm -syn, thiab tseem nyob ntawm mitochondrial homeostasis. Txawm hais tias -syn feem ntau tam sim no nyob rau hauv cytosolic eosinophilic LBs, nws kuj tau kuaj pom hauv mitochondria, lysosomes, thiab lwm yam organelles hauv post-mortem PD hlwb. Lub xub ntiag ntawm LBs nyob rau hauv lub peripheral, enteric, thiab central nervous systems (CNS) tau cuam tshuam rau ob qho tib si lub cev muaj zog thiab tsis yog lub cev muaj zog cov tsos mob ntawm PD [17,18].muab cistancheCov kev hloov pauv hauv qhov -syn ib ntus lossis lwm yam kev thuam ntawm pathological ua rau tsim cov oligomers, uas tej zaum yuav pab pawg ua ke loj dua. Cov aggregates no tuaj yeem hloov ntau txoj hauv kev ntawm cov cellular thiab molecular hauv cov neurons - tshwj xeeb nrog cov txheej txheem autophagy thiab proteasomal, xws li kev ua haujlwm mitochondrial, vesicle trafficking, organelle, thiab protein degradation - tag nrho cov no ua rau cov neurodegeneration. Tom qab ntawd, raws li qhov tshwm sim ntawm neurodegeneration, o-syn aggregates tau tso rau hauv SN, qhov chaw uas lawv qhib microglia [19]. Qhov kev tswj tsis tau qhov no tuaj yeem ua rau muaj cov teeb meem tshwm sim [20] uas tuaj yeem ua rau muaj kev puas tsuaj ntxiv thaum lub sijhawm tseem ceeb tau mus txog.

Cistanche tuaj yeem tiv thaiv kev laus

2.1.Neuropsychiatric Manifestations ntawm PD

Tsis muaj ib qho kev sim tshwj xeeb los kuaj xyuas PD. Yog li ntawd, kev kuaj mob yog raws li keeb kwm kho mob, tshuaj xyuas cov tsos mob thiab cov tsos mob, thiab kev kuaj mob hlwb thiab lub cev (Box1). Cov cim qhia ntawm lub cev muaj zog ntawm PD feem ntau pib nyob ib ncig ntawm 60 xyoo ntawm hnub nyoog [21], tab sis YOPD tsis tshua muaj, tshwj xeeb tshaj yog nyob rau hauv qee hom kab mob [22]. Unilateral lossis asymmetric bradykinesia thiab / lossis so tremors yog thawj cov tsos mob ntawm tus kab mob [23]. So tremor yog tam sim no nyob rau hauv cov nqaij ntshiv thiab ploj mus thaum ua haujlwm thiab pw tsaug zog. Tej zaum nws yuav nce los ntawm kev xav ntawm kev xav. Bradykinesia, txhais los ntawm qhov qeeb ntawm kev txav mus los thiab txo qis amplitude lossis nrawm, ua rau muaj teeb meem nrog kev txav rov ua dua, micrography, me-kauj ruam mus, thiab hais lus nyuaj (hypophonia thiab dysarthria), uas yuav tshwm sim thaum tus kab mob hloov zuj zus.cistanchRigidity yuav ua rau mob thiab ua rau lub cev deformity (thoracolumbar spinal flexion). Kev loj hlob qeeb nrog ob sab txuas ntxiv ntawm akinesia, tshee, thiab hypertonia, tom qab ntawd los ntawm kev tsis sib haum xeeb ntawm lub cev, khov ntawm kev taug kev, ntog, thiab qee tus neeg mob, camptocormia. Qee cov cim tsis yog lub cev muaj zog (premotor) yuav tshwm sim ntau xyoo ua ntej thawj cov tsos mob ntawm lub cev muaj zog; cov no muaj xws li kev nyuaj siab, hyposmia, cem quav, los yog ceev-qhov muag-mus pw tsaug zog mob [24]. Kev ntxhov siab thiab apathy tuaj yeem tshwm sim los ntawm qhov pib ntawm PD, qhov hnyav dysautonomia (orthostatic hypotension, urinary dysfunction vim detrusor hyperactivity), kev pw tsaug zog fragmentation, kev paub tsis meej (dysexecutive disorders), thiab hallucinations tshwm sim tom qab, thiab yuav ua rau poob ntawm autonomy. 24, 25] ib.

2.2. Kev kho tam sim no rau PD thiab Kev Tswj Xyuas Kho Mob

Kev kho cov tsos mob yog tib txoj kev kho mob tam sim no muaj [26], nrog rau kev kho mob txhawm rau them nyiaj rau qhov tsis txaus dopaminergic. Dopaminergic tshuaj (levodopa txuam nrog dopa-decarboxylase inhibitor, dopaminergic agonists, los yog monoamine oxidase-type B inhibitors), siv nyob rau hauv ib tug neeg los yog nyob rau hauv poly-therapy regimens, yog heev npaum nyob rau hauv thaum ntxov theem ntawm tus kab mob. Txawm li cas los xij, kev tswj hwm yuav nyuaj dua li lub xyoo kev vam meej. Tseeb tiag, kev kho mob dopaminergic, uas txhim kho cov cim qhia lub cev muaj zog, tuaj yeem muaj teeb meem tsis zoo. Ib qho tshwm sim hnav-tawm (qhov kawg ntawm koob tshuaj tsis ua haujlwm) thiab dyskinesia tshwm sim tom qab ob peb xyoos ntawm kev kho mob levodopa [27] .Impulse tswj kev mob (pathological kev twv txiaj lossis kev mus yuav khoom, kev sib deev siab; [28], kev hnov ​​​​lus, lossis kev puas siab puas ntsws kuj tuaj yeem cuam tshuam kev kho dopaminergic, thiab feem ntau ntsib nrog dopamine agonists [29]. Lwm yam kev kho mob, suav nrog catechol-O-methyltransferase inhibitors los kho cov kev hloov pauv ntawm lub cev lossis amantadine rau dyskinesia [26] tuaj yeem siv tom qab thaum tus kab mob nce ntxiv. ntawm apomorphine, nruam jejunal kev tswj hwm ntawm droxidopa gel, ob sab subthalamic nuclear stimulation) yog npaj thaum lub cev muaj zog hloov pauv thiab dyskinesia ua qhov tseem ceeb [30]. Cov kev kho mob no tsom kom ua tiav striatal dopaminergic stimulation tab sis tsis muaj kev cuam tshuam rau kev loj hlob ntawm tus kab mob. Tsis tas li ntawd, qee cov tsos mob axial. (dysarthria, postural instability) tsis yog dopa-rhiab heev, thiab kev tswj xyuas kev kho mob tsis yog lub cev muaj zog Cov tsos mob tseem nyuaj [31,32].

Ntau xyoo ntawm kev tshawb nrhiav tau coj mus rau kev txhim kho cov tswv yim kho mob, uas tau ua kom zoo dua qub rau cov neeg mob. Txawm li cas los xij, kev ua kom tus kab mob qeeb qeeb tseem tseem yog qhov nyuaj, thiab qhov tseem ceeb tsis tu ncua [33], thiab cov kab mob tshiab-hloov kho tau zoo siab tos txais [3,34]. Txawm hais tias lub luag haujlwm ntawm proteasome thiab autophagy, suav nrog macroautophagy thiab chaperone-mediated autophagy (CMA), tau paub ntev los pab txhawb rau -syn clearance [35,36l, dysregulation ntawm cov txheej txheem no tseem tsis to taub hauv PD.cistanche AustraliaNtau qhov kev hloov pauv ntawm cov noob thiab kev hloov pauv rau cov protein uas koom nrog hauv PD yog sib txuas nrog autophagy, tshwj xeeb tshaj yog mitophagy thiab autophagy-lysosomal txoj hauv kev. Hauv qhov kev tshuaj xyuas no, peb tsom mus rau kev koom tes ntawm autophagy hauv PD, tawm tswv yim rau cov lus nug tseem ceeb hauv cheeb tsam thiab nthuav tawm cov lus qhia tshiab rau cov kev kho mob uas muaj peev xwm tsom mus rau txoj hauv kev autophagy.

3. Autophagy

Autophagy yog ib qho tseem ceeb ntawm cov kab mob hauv cov cellular degradation uas cov ntaub ntawv cytoplasmic raug xa mus rau lysosome rau degradation. Raws li txoj hauv kev uas cov ntsiab lus xa mus rau lysosomes, ntau hom autophagy tau raug txhais. Cov ntaub ntawv sib txawv no kuj muaj qhov sib txawv ntawm kev xaiv rau cov khoom thauj (Table 1; Daim duab 2). Peb yam tseem ceeb ntawm cov txheej txheem autophagy yog macroautophagy, CMA, thiab microautophagy / EMI. Txawm li cas los xij ntawm txoj kev xa khoom, lub luag haujlwm tseem ceeb ntawm cov txheej txheem no yog txhawm rau txo qis kev sib raug zoo ntawm tus khub-rial uas tsis zoo, tej zaum yuav muaj kuab lom, lossis tau tsim ntau dhau, thiab yog li tswj hwm cell homeostasis.

3.1.The Autophagy Machinery

Cov txheej txheem ntawm autophagy tau raug tshawb xyuas thiab tau tshuaj xyuas kom meej los ntawm ntau tus kws sau ntawv [61-63]. Cov yam ntxwv dav dav ntawm peb txoj hauv kev tau nthuav tawm hauv daim duab 2. Kev nce qib tsis ntev los no ntsig txog cov txheej txheem canonical thiab non-canonical autophagic cov txheej txheem-tshwj xeeb tshaj yog nyob rau hauv cov tsiaj txhu-tau ntxiv rau peb txoj kev nkag siab txog cov txheej txheem uas yuav ua lub luag haujlwm tseem ceeb hauv cov kab mob neurodegenerative xws li PD. Txawm li cas los xij, ntau qhov kev tshawb pom molecular uas peb tam sim no nkag siab txog kev tswj hwm ntawm autophagy yog tsim los ntawm kev txheeb xyuas cov poov xab. Hauv cov hlwb, peb hom autophagy coexist thiab ua lub luag haujlwm tseem ceeb hauv kev tswj hwm cellular homeostasis. Txawm li cas los xij, feem ntau ntawm cov txiaj ntsig muaj nyob hauv daim teb no cuam tshuam nrog macroautophagy. Cov txheej txheem no tau muab faib ua cov kauj ruam hauv qab no: nucleation, elongation, autophagosome tsim, autophagosome-lysosome fusion, thiab degradation (Daim duab 2). Txhua kauj ruam yog kev tswj hwm caj ces zoo thiab ua nws lub luag haujlwm tshwj xeeb hauv kev tswj hwm qhov xwm txheej ntawm cov txheej txheem. Piv txwv li, ib tug xov tooj ntawm conserved autophagy-related proteins ua nyob rau hauv ib tug hierarchical yam rau kho kom haum autophagosome tsim. Thaum cov dej ntws tawm induction, cov tshuab autophagy tuaj rau hauv kev sib cuag nrog cov kab sib cais / phagophore. Lub hauv paus pib thaum ntxov thiab qhov tseem ceeb ntawm qhov chaw endoplasmic reticulum (ER), Golgi complex, endosomes, thiab mitochondria] ntawm lub nascent cais daim nyias nyias tseem yog ib qho teeb meem ntawm kev sib cav [64]. Ib txoj kev tshawb fawb ultrastructural uas muaj kev sim electron microscopy tau lees paub tias qhov tshwj xeeb subdomain ntawm ER pab txhawb rau phagophore tiam [65]. Txog 40 autophagy-related (ATG) cov protein tau raug txheeb xyuas tias muaj kev koom tes hauv cov txheej txheem dynamic no, lawv tau ua raws hierarchically, pib los ntawm kev pib ntawm cov txheej txheem thiab kev loj hlob mus txog rau kev loj hlob ntawm autophagosomes. Cov proteins no ua haujlwm ua ke hauv ntau qhov chaw ua haujlwm, tshwj xeeb (i)Unc{{11}xws li kinase 1(ULK1)/ATG1 kinase complex; (ii) chav kawm II phosphatidylinositol (PI)3-kinase complex;(ii)the PI(3)P-binding ATG2-ATG18 complex;(iv) ob lub conjugation systems (ATG12 conjugation system thiab microtubule-associated protein 1A/1B-light chain 3(MAP1LC3)/ATG8 conjugation system); thiab (v) fusion machinery (Daim duab 2).

Qhov tseeb, ntau lub npe hu ua ATG proteins muaj lwm txoj haujlwm tshaj li autophagy [66]. Yog li, piv txwv li, MAP1LC3 lipidation (ib lub tswv yim uas tau siv ntev los ntsuas kev ua haujlwm ntawm autophagic [67,68]) kuj tseem koom nrog hauv cov txheej txheem tsis-autophagic cellular xws li phagocytosis, LAP, micropinocytosis, lossis kab mob kis. Cov txheej txheem no hu ua non-canonical autophagic txheej txheem [69]. Hauv cov txheej txheem uas tsis yog-canonical no, cov haujlwm uas tseem tsis tau ua tiav [70,71] MAP1LC3 conjugates rau ib leeg-branes (ib daim nyias nyias ATG8 conjugation, SMAC), thiab cytosolic constituents tsis xa mus rau lysosome [72].

3.2. Neuronal Autophagy Pab txhawb rau Neuronal Physiology

Muaj pov thawj txaus los txhawb lub tswv yim tias neuronal autophagy plays lub luag haujlwm txiav txim siab hauv ntau yam ntawm kev txhim kho neuron thiab khaws cia cov haujlwm ntawm neuronal [73-75]. Hauv cov hlwb tom qab mitotic zoo li neurons, autophagy yog qhov tseem ceeb tshwj xeeb rau kev ciaj sia thiab homeostasis, vim tias cov hlwb no tsis tuaj yeem tshem tawm cov tshuaj lom thiab cov kab mob puas tsuaj thaum lub sijhawm cell faib. Autophagy, nrog rau cov kab ke proteasomal [76], yog li ntawd yog ib qho tseem ceeb ntawm kev tswj xyuas zoo uas ua kom lub neej ntev ntawm cov hlwb neuronal. Presynaptic autophagy nyob rau hauv lub axon davhlau ya nyob twg kuj tseem ceeb heev rau synaptic txij nkawm thiab plasticity [77].

Ntawm cov paj hlwb, tsuas yog cortical neurons, Purkinje hlwb, thiab hypothalamic neurons tuaj yeem nce lawv cov ntsiab lus autophagosome raws li kev txhawb nqa. Cov laj thawj meej rau qhov niche mechanism tam sim no tsis paub [62,78]. Ib qho kev piav qhia tau yog qhov tsis tseem ceeb thiab muaj feem xyuam rau qhov tseeb tias, zoo li rau qee yam ntawm tes, ntsuas autophagy hauv neurons, tshwj xeeb tshaj yog nyob rau hauv lub hlwb, tseem nyuaj [79,80]. Xwb, vim cov paj hlwb tau sib txawv ntawm qhov sib txawv - nrog lub peev xwm rov ua dua tshiab dua li lwm cov hlwb - lawv tsis tshua muaj autophagic. Txawm li cas los xij, kev tshawb fawb ntawm lub hlwb los ntawm cov nas uas tsis muaj autophagy tau muab pov thawj tias sequestosome-1 (SQSTM1)/p62 proteins thiab polyubiquitinated proteins nyob rau hauv feem ntau cov hlwb hlwb [81]. Hauv qhov sib piv, SQSTM1 tsis muaj peev xwm ua rau tsis muaj qhov ua tiav ntawm autophagy. Nws tshwm sim yog li ntawd cov ntsiab lus autophagosome nyob ntawm hom hlwb thiab hom kev ntxhov siab.

3.3. Cov kab mob autophagy thiab neurodegenerative

Raws li tau hais los saum toj no, txhawm rau tiv thaiv cov neuronal thiab synaptic tsis ua haujlwm, cov neurons tau hloov kho cov txheej txheem los tshem tawm cov tshuaj lom thiab cov khoom tsis zoo thiab cov organelles. Cov txheej txheem no yog qhov tseem ceeb los tswj kom muaj qib siab ntawm neurotransmission thiab kev ncaj ncees ntawm kev ua haujlwm proteome hauv neurons. Autophagy yog lub hauv paus rau qhov kev tiv thaiv no. Hnub nyoog cuam tshuam txog kev ua haujlwm poob ntawm autophagy ua rau cov neurons yooj yim rau kev ntxhov siab thiab tuaj yeem ua rau cell tuag [82]. Pathological cuam tshuam ntawm txoj hauv kev autophagy tuaj yeem ua rau muaj cov kab mob neurodegenerative uas tej zaum yuav lossis tsis cuam tshuam rau kev laus.

Kev cuam tshuam autophagy tau raug sau tseg hauv ntau cov kab mob neurodegenerative, suav nrog PD, Alzheimer's disease (AD), Huntington's disease (HD), thiab amyotrophic lateral sclerosis (ALS) (rau kev tshuaj xyuas dav dav, saib [63.84]). Kev tshawb xyuas cov txheej txheem txuas autophagy rau cov kab mob no, nws tau raug pom, piv txwv li, cov nas tshwj xeeb tsis txaus rau Atg5 hauv cov hlwb neural txhim kho qhov tsis txaus ntawm lub cev muaj zog thaum tseem khaws cov cytoplasmic suav nrog lub cev hauv neurons [85]. Ib yam li ntawd, hauv cov nas uas tsis muaj Atg7, Atg5, lossis Ambral, ubiquitin tau pom muaj nyob rau hauv CNS, thiab cytoplasmic inclusions tau cuam tshuam nrog lub cev muaj zog, thiab cov hlab ntsha neuronal tsis zoo hauv nas embryos [86]. Kev hloov pauv ntawm cov noob txuas nrog cov txheej txheem autophagic - piv txwv li, SQSTM1, optineurin / OPTN, E3 ubiquitin ligase PARKIN / PRKN, PINK1, TBK1 - kuj tau cuam tshuam rau ntau yam kab mob neurodegenerative. Tshwj xeeb, qhov tsis xws luag hauv mitophagy uas tseem pom hauv cov kab mob tshwj xeeb thiab cov kab mob hauv lub cev, tau raug sau tseg hauv cov kab mob neurodegenerative [87]. Ntxiv nrog rau cov kev hloov caj ces, kev hloov pauv tseem ceeb rau kev qhia cov protein tau txuas nrog cov kab mob neurodegenerative. Piv txwv li, kev qhia txawv txav ntawm cov protein glandular epithelial cell 1 (GABARAPL1 / GEC1) tau cuam tshuam nrog cov kab mob neurodegenerative [88]. 3.4. Autophagy thiab Parkinson's Disease

Ntawm cov kab mob pathological ntawm PD yog LBs uas muaj qhov txawv txav -syn protein. Kev hloov pauv lossis triplication ntawm cov noob encoding -syn (SNCA) tsis tshua muaj tab sis tau koom nrog kev pib thiab kev loj hlob ntawm PD. Interestingly, ib qho tsis ua hauj lwm cuam tshuam rau ib qho ntawm cov txheej txheem degradative, ncaj qha lossis tsis ncaj, cuam tshuam rau lwm cov txheej txheem autophagy. Lub ubiquitin-proteasome system (UPS) paub tias yog thawj txoj kev degradative rau monoubiquitinated -syn, whereas txoj kev macroautophagy degrades deubiquitinated a-syn [89,90]. Hauv PD, yog li ntawd, ob qho tib si mitochondria thiab lysosomes ua lub luag haujlwm tseem ceeb (Daim duab 3). 3.4.1.Role of Mitophagy hauv PD

Raws li lub zog tsim cov organelle, mitochondrion yog lub hauv paus rau ntau yam kab mob neurodegenerative, suav nrog PD [91-95]. Ntau qhov kev tshawb nrhiav tau qhia tias kev hloov pauv caj ces cuam tshuam nrog PD (xws li PRKN, PINK1, thiab lwm yam) kuj tseem txuas nrog cov kab mob mitochondrial, nrog rau kev tsis xws luag hauv mitophagy (Table 2) [9]. Hom kev puas tsuaj tshwm sim rau mitochondria ib txwm nyob ntawm hom a-syn (kev sib sau ua ke lossis tsis yog, ua los ntawm cov ntawv hloov pauv lossis ib txwm nyob ntawm SNCA). Cov kev tshawb fawb ntxiv tau lees paub tias o-syn cuam tshuam rau kev sib cuam tshuam ntawm mitochondria-associated membrane nrog ER. Qhov kev sib cuam tshuam no ua lub luag haujlwm tseem ceeb hauv kev tswj Ca4 ntxiv rau kev taw qhia thiab apoptosis. Tsis tas li ntawd, o-syn txawv txav cuam tshuam nrog peroxisome proliferator-activated receptor-gamma coactivator 1-alpha, uas ua lub luag haujlwm tseem ceeb hauv mitochondrial biogenesis thiab hauv apoptosis. Mitochondrial dysfunction nrog kev koom tes ntawm cov yam ntxwv muaj feem xyuam rau a-syn tau sib tham txog lwm qhov [9,97,98].

Daim duab 3. Autophagy impairment hauv PD. Cov ntaub ntawv tsis zoo ntawm autophagy tau pom hauv PD. Genetic mutations ntawm -syn yog txuas rau kev puas tsuaj ntawm cov txheej txheem autophagy. Ntau yam, xws li caj ces, kev lag luam mitochondrial tsis zoo, oxidative stress, dysfunctional ATP cycle, deregulated mitochondrial dynamics, thiab hloov mitogenesis perturb noj qab nyob zoo mitochondria. Kev puas tsuaj / ua haujlwm tsis zoo mitochondria tso cai PINK1 los nrhiav PRKN, uas tig mus ua kom muaj lwm cov proteins tseem ceeb, xws li OPTN thiab ubiquitin, Rab7, thiab lwm yam yog li pib ua cov txheej txheem tswj kom zoo, piv txwv li, mitophagy. Lub luag haujlwm ntawm Rab7 yog tswj hwm los ntawm TBC1D15/17 (tseem yog TBC tsev neeg nrog Rab-GAP lub luag haujlwm), uas tseem tswj hwm cov kev ua haujlwm thiab lub hom phiaj ntawm cov ntawv sib cais los ntawm kev sib txuas nrog Fis1 thiab MAP1LC3B. Cov kauj ruam ua ntu zus ntawm mitophagy yog tsim ntawm phagophore, maturation rau hauv mitoautophagosome, thiab fusion ntawm mitoautophagosome nrog lysosome. Pa autophagy kuj plays lub luag haujlwm tseem ceeb hauv (ob leeg naive thiab aggregated) -syn degradation. x-syn xaiv khi rau cov kab mob-paub paub receptor, TLR-4, uas ua rau txoj hauv kev qis qis tom qab NF-kB ua kom, txhawm rau txhawb nqa SQSTM1/p62 ntau lawm. Lub SQSTM1 tsim khi rau lub internalized -syn thiab pib cov txheej txheem autophagy. Dysregulation ntawm cov txheej txheem autophagy ua rau cov tsub zuj zuj ntawm -syn ib sab SQSTM1. Sib nrug los ntawm mitophagy thiab macroautophagy, CMA kuj xaiv degrades -syn, uas muaj KFERQ zoo li motif. Xaiv CMA inhibition lossis hloov CMA ua haujlwm cuam tshuam -syn degradation. Cov ntawv luv luv tsis tau piav qhia hauv cov ntawv nyeem: Sau, Mitochondrial fission 1 protein; GAP, GTPase-activating proteins; IKK, IkB kinase; MyD88, myeloid sib txawv protein 88; Rab, Ras superfamily ntawm me G proteins; TBC, Tre-2/Bub2/Cdc16; TIRAP, Tus Xov Tooj-interleukin 1 receptor adapter protein.

Kev tsis xws luag hauv txoj kev mitophagy, tshwj xeeb tshaj yog PARK2 (PRKN kev hloov pauv) thiab PARK6 (PINK1 kev hloov pauv), tau raug npaj ua qhov tseem ceeb ntawm tsev neeg PD. Nyob rau hauv kev noj qab nyob zoo, PINK1, uas nyob rau hauv lub mitochondrion, yog translocated mus rau hauv lub mitochondrial puab membrane qhov twg nws yog degraded. Nyob rau hauv tej yam kev mob uas tsis paub, mitochondria ua puas thiab poob daim nyias nyias (Daim duab 3). Qhov no ua rau PINK1 ua kom muaj zog thiab kev nrhiav neeg ua haujlwm ntawm PRKN, uas yuav pab txhawb mitophagy thaum ua rau lwm cov mitochondrial membrane proteins OPTN thiab nuclear dot protein 52-kDa (NDP52) [62,119-124]. PRKN kev hloov pauv yog feem ntau ua rau autosomal recessive YOPD, ua raws li kev hloov pauv hauv PINK1. Nrog rau nws lub luag haujlwm hauv mitophagy, PRKN ua lub luag haujlwm tseem ceeb hauv kev ua lipid thiab kev nthuav dav ntawm GTPase Rab7, uas tswj cov lysosomal dynamics [125-128]. PRKN deficiency ua rau DA neuronal degeneration nyob rau hauv nas, thiab embryonic fibroblasts muab los ntawm PINK1-cov nas tsis muaj peev xwm qhia lysosomal dysfunction [129]. Tsis tas li ntawd, kev hloov pauv hauv PINK1 thiab PRKN ua rau muaj qhov tsis xws luag hauv cov txheej txheem mitophagy [62]. Txawm li cas los xij, kev tshawb fawb tseem tsis tau piav qhia vim li cas PRKN tsis raug xaiv rau mitochondria hauv DA neurons nyob rau hauv cov xwm txheej depolarized [130]. Qhov tshwm sim ntawm mitophagy dysfunctions nyob rau hauv neurons yog uncontrolled stress (ie, tiam ntawm reactive oxygen hom), uas ua rau neuronal cell tuag. Nyob rau hauv txoj kab nrog cov txiaj ntsig no, kev tsom mus rau cov teeb meem mitophagy tuaj yeem muaj txiaj ntsig zoo hauv PD. Nws tau pom, piv txwv li, tias tus inhibitor ntawm mitochondrial deubiquitinase USP30, uas tsis zoo tswj PRKN-mediated mitophagy, xaiv mitophagy flux, yog li nws tuaj yeem yog qhov txaus siab rau kev txhim kho cov kev kho tshiab [131,132].

Ntxiv rau qhov cuam tshuam loj ntawm PINK1 thiab PRKN kev hloov pauv, SNCA kev hloov pauv tau kawm hauv cov ntsiab lus ntawm mitophagy. -syn cuam tshuam nrog Miro proteins (sab nraud mitochondrial membrane adapter proteins, muaj txiaj ntsig zoo hauv mitochondrial motility) thiab cuam tshuam nrog cov txheej txheem Miro degradation, uas yog ib qho tseem ceeb hauv cov txheej txheem mitophagy [133]. Kev tshawb fawb hauv nas thiab poov xab harboring mutations hauv SCNA tau lees paub lub luag hauj lwm ntawm -syn nyob rau hauv neuronal tuag, ntawm mitochondrial dysfunction [134,135].

Lub transcription factor myocyte enhancer factor 2D (MEF2D) yog lwm qhov tseem ceeb mitochondrial regulator (Table 2). Nws yog ib qho tseem ceeb hauv kev sib kis ntawm cov teeb liab extracellular thiab ua kom cov kev pab cuam caj ces nyob rau hauv teb rau ntau yam stimuli nyob rau hauv ntau hom cell, nrog rau cov neurons. MEF2D yog tus tswj hwm tseem ceeb ntawm IL-10 gene qhia, koom nrog kev tswj tsis zoo ntawm microglial inflammatory teb, thiab tiv thaiv inflammatory-mediated cytotoxicity [136]. Kev txo qis MEF2Dexpression tau txuas ncaj qha rau kev txo qis ntawm nicotinamide adenine dinucleotide dehydrogenase 6 (NADH) ib feem ntawm mitochondrial complex I. Post-mortem tsom xam ntawm lub hlwb kuaj los ntawm PD cov neeg mob tau qhia txo qis ntawm MEF2D thiab NADH [137].

Ib tug xov tooj ntawm lwm yam kev hloov pauv caj ces, suav nrog qhov tsis txaus ntawm mitochondrial apoptosis-inducing factor (AF) thiab mitochondrial transcription factor A (TFAM; [138] uas cuam tshuam txoj hauv kev endo-lysosomal, kuj cuam tshuam rau mitochondrial physiology thiab kev ua haujlwm, ua rau piv txwv rau kev puas tsuaj mitophagy, Kev ua haujlwm tsis zoo oxidative phosphorylation, deregulated mitochondrial dynamics, hloov mitogenesis, calcium imbalance, hloov mitochondrial trafficking, thiab induction ntawm oxidative stress (Table 2). ubiquitin ligase-mediated pathways [97,139,140]. Tam sim no tsis tau paub txog tias txoj hauv kev no txuas rau PD li cas.

Kab lus no yog muab rho tawm los ntawm Cells 2021, 10, 3547. https://doi.org/10.3390/cells10123547 https://www.mdpi.com/journal/cells