Pathogenic Mechanism Ntawm -synuclein hauv HiPSC Tus Qauv Ntawm Parkinson's Disease

Abstract

-synuclein yog ib qho tseem ceeb ntawm cov neeg ua si hauv pathology ntawm ntau yam mob neurodegenerative. Parkinson's disease (PD) yog ib qho kev puas siab puas ntsws neurodegenerative uas cuam tshuam feem ntau ntawm dopaminergic (DA) neurons hauv substantia nigra ntawm lub hlwb. Ib yam ntawm PD pathology yog qhov kev tshawb pom ntawm cov protein aggregations hu ua 'Lewy cev' nyob rau hauv cov cheeb tsam ntawm lub hlwb cuam tshuam. -synuclein cuam tshuam rau ntau lub xeev cov kab mob suav nrog kev dementia nrog Lewy lub cev (DLB) thiab Alzheimer's kab mob. Txawm li cas los xij, PD yog cov synucleinopathy feem ntau thiab tseem yog qhov tseem ceeb ntawm kev tshawb fawb PD nyob rau hauv cov nqe lus ntawm -synuclein Lewy lub cev pathology. Kev hloov pauv hauv ntau cov noob yog txuam nrog PD txoj kev loj hlob nrog rau SNCA, uas encodes -synuclein. Ntau yam qauv qauv tau ua haujlwm los kawm -synuclein physiology thiab pathophysiology hauv kev sim ua kom muaj kev sib raug zoo rau PD pathology. Cov qauv no suav nrog cov xov tooj ntawm tes thiab tsiaj cov tshuab tshawb nrhiav cov thev naus laus zis hloov pauv, kab mob vector qhia, kev ua kom zoo, thiab cov qauv los kawm txog qhov muaj peev xwm prion protein zoo li cuam tshuam ntawm -synuclein. Kev tshuaj xyuas tam sim no tsom rau tib neeg induced pluripotent qia cell (iPSC) cov qauv nrog rau kev tsom mus rau kev hloov pauv lossis kev sib npaug ntawm SNCA noob. iPSCs yog cov thev naus laus zis hloov zuj zus sai nrog cov lus cog tseg loj hauv kev kawm txog lub cev ib txwm muaj thiab kab mob ua qauv hauv vitro. Lub peev xwm los tuav tus neeg mob cov keeb kwm yav dhau los thiab rov ua cov phenotypes zoo sib xws ua rau iPSCs yog cov cuab yeej muaj zog hauv kev kawm txog cov kab mob neurological. Qhov kev tshuaj xyuas no tsom mus rau qhov kev paub tam sim no txog -synuclein physiological muaj nuj nqi nrog rau nws lub luag haujlwm hauv PD pathogenesis raws li tib neeg iPSC qauv.

Ntsiab lus

- synuclein pathogenesis; hiPSC qauv; Tus kab mob Parkinson; Cov kab mob neurodegenerative;Cov txiaj ntsig Cistanche.

Nyem qhov no mus yuavCistanche ntxiv

Taw qhia

Cov kab mob neurodegenerative yog ib pawg ntawm cov kab mob loj zuj zus uas tshwm sim los ntawm kev tuag ntawm cov cell neuronal, tsis suav nrog cov xwm txheej feem ntau cuam tshuam nrog ischemia, kab mob, lossis malignancy [1]. Cov kab mob neurodegenerative yog cov kab mob uas muaj feem cuam tshuam txog hnub nyoog tshaj plaws hauv tib neeg, ua ntau zuj zus thiab cuam tshuam rau ntau lab tus tib neeg thoob ntiaj teb. Txawm hais tias muaj kev tshawb fawb txog kev tshawb fawb thiab kev kho mob tseem ceeb, cov kev kho mob zoo tseem tsis muaj. Yog li, nws yog ib qho tseem ceeb heev los txuas qhov tsis sib xws hauv peb txoj kev nkag siab ntawm cov txheej txheem physiological thiab pathological hauv qab neurodegeneration los pab txhawb kev txhim kho cov phiaj xwm kev kho mob zoo. Hauv 25 xyoo dhau los, ntau lub cellular thiab molecular mechanisms tau txheeb xyuas uas cuam tshuam nrog neuronal degeneration, qhov tseem ceeb ntawm cov no yog protein aggregate deposition [2], mitochondrial DNA mutations [3], thiab oxidative stress [4]. Kev tsim cov kab mob sib txawv ntawm lub cev nqaij daim tawv tau txais txiaj ntsig zoo thiab tau pom tias yog ib qho tseem ceeb rau ntau yam kab mob neurodegenerative, uas tam sim no tau muab faib ua cov npe hu ua proteinopathies [5]. Neurodegenerative proteinopathies sawv cev rau ib pab pawg ntawm cov kab mob uas tau txhais los ntawm kev sib sau ua ke tsis tsim nyog, tso tawm, thiab / lossis sib sau ntawm cov protein ib txwm muaj uas muaj qhov tseem ceeb ntawm lub cev muaj zog. Proteinopathies raug cais raws li cov protein tseem ceeb hauv cov deposits, yog li, tauopathies muaj feem ntau τ protein, thiab TDP-43 proteinopathies muaj TDP-43 [6]. -synuclein yog ib tug tswv cuab tseem ceeb ntawm pab pawg no ntawm cov proteins koom nrog cov kab mob neurodegenerative.

-synuclein tau pom tias ua lub luag haujlwm tseem ceeb hauv pathology ntawm ntau yam ntawm cov kab mob neurodegenerative, pab pawg ua synucleinopathies. -synuclein encoded los ntawm SNCA noob uas pom ntawm chromosome 4 (4q21.3-22) thiab kev hloov pauv hauv cov noob no qhia txog autosomal dominant qauv ntawm kev qub txeeg qub teg. Kev hloov pauv hauv cov noob no tau pom tias ua rau -synuclein tsub zuj zuj thiab sib sau ua ke uas tshwm sim hauv ntau hom neurodegenerative mob [7-9]. Cov kab mob uas paub zoo xws li Parkinson's disease (PD), dementia nrog Lewy lub cev (DLB), thiab ntau yam kab mob atrophy (MSA) raug ntes nyob rau hauv pab pawg no, nrog rau cov kab mob tsis tshua muaj xws li neuroaxonal dystrophies, ntshiab autonomic tsis ua hauj lwm (PAF) los yog REM pw tsaug zog tsis zoo [10].

Tam sim no, muaj ntau qhov dav ntawm cov qauv qauv muaj los pab hauv kev kawm ntawm synucleinopathies. Cov qauv tsiaj muab cov ntaub ntawv tseem ceeb txog kev hloov pauv tus cwj pwm cuam tshuam nrog kev hloov pauv hauv neuronal, tab sis hom kev sib txawv tsim teeb meem kom tau txais tib neeg txhais cov kab mob tshwj xeeb phenotypes. Cov qauv cellular muaj qhov zoo ntawm kev tso cai rau cov kab mob pathology kom loj hlob sai, raug nqi zoo, thiab tuaj yeem ua tau yooj yim dua los ntawm cov noob caj noob ces, tau txais kev txaus siab, tshwj xeeb tshaj yog nyob rau hauv cov kev tshawb fawb molecular thiab cellular. Hauv 14 xyoo dhau los, qhov tshwm sim ntawm induced pluripotent qia cell (iPSC) thev naus laus zis tau ua rau peb nkag siab txog cov neeg mob tshwj xeeb cov txheej txheem molecular ntawm tus kab mob, nrog rau kev txhim kho cov kev kho tshiab thiab tshuaj ntsuam xyuas tshuaj. Cov thev naus laus zis no yog tsim los ntawm kev muaj peev xwm rov ua cov kab mob tshwj xeeb ntawm tus neeg mob fibroblasts los ntawm kev yuam cov lus qhia tshwj xeeb ntawm kev hloov pauv (feem ntau, Oct4, Sox2, cMyc, thiab Klf4), ua rau lub xeev pluripotent. Tom qab ntawd, cov pluripotent hlwb tau sib txawv rau hauv cov hlwb somatic paub tab ntawm kev txaus siab [11]. Hom kev mus kom ze no feem ntau hu ua 'kab mob hauv lub tais' qauv [12] (Daim duab 1). Cov txheej txheem no muaj qhov zoo ntawm kev tswj tus neeg mob cov keeb kwm yav dhau los thiab tso cai rau kev cuam tshuam ntawm qee qhov kev hloov pauv tseem ceeb ntawm pathophysiology tau kawm, tso cai rau tus cwj pwm ntawm cov cellular hloov pauv-raws li phenotypes hauv cov kab mob nyuaj xws li PD [13].

Dopaminergic (DA) neurons yog hom xov tooj tseem ceeb siv los kawm txog neurodegeneration hauv PD siv ntau txoj cai sib txawv. Feem ntau cov kev cai cuam tshuam nrog qhov yuam kev ntawm LMX1A, uas encodes ib qho kev hloov pauv tseem ceeb rau ventral midbrain tus kheej, noj dual-SMAD inhibition mus kom ze. Cov txheej txheem no yog ua raws li kev siv cov tshuaj Noggin thiab SB431542 ua cov tshuaj tiv thaiv ntawm cov teeb liab-transducer protein tsev neeg SMAD (ib qho lus hais los ntawm kev sib xyaw ntawm Caenorhabditis elegans SMA noob thiab Drosophila MAD, Cov Niam Txiv tiv thaiv decapentaplegic), uas yog cov tswj hwm tseem ceeb ntawm cell loj hlob [14–16]. Tsis ntev los no, kev sib txawv tuaj yeem raug coj los ntawm kev quab yuam overexpression ntawm yam ASCL1, NURR1, thiab LMX1A [17]. Lub reprogramming ntawm PD cov neeg mob hlwb thiab sib txawv rau DA neurons tau raug tshuaj xyuas ntau qhov chaw [18,19].

Kev lees paub cov ntaub ntawv tseem ceeb uas iPSC qauv muab thiab qhov tseem ceeb ntawm -synuclein hauv neurodegeneration, qhov kev tshuaj xyuas no yuav tsom mus rau cov kev paub tau los ntawm kev kawm SNCA kev hloov pauv hauv iPSC qauv tshuab, tshawb nrhiav -synuclein aggregation thiab toxicity. Hauv cov ntsiab lus no, qee cov lus nug tseem ceeb yuav tau tham txog: Puas yog kev hloov pauv hauv SNCA gene tsuas yog instigator ntawm -synuclein aggregation? Dab tsi yog cov kab mob tshwm sim ntawm SNCA kev hloov pauv txawv ntawm -synuclein aggregation?

-synuclein: qauv thiab kev ua haujlwm ntawm lub cev

Raws li cov ntaub ntawv tseem ceeb, -synuclein yog ib qho 14-kDa protein, ubiquitously qhia nyob rau hauv presynaptic terminals ntawm lub hlwb, feem ntau nyob rau hauv excitatory neurons, thawj zaug qhia nyob rau hauv 1988 [20]. Cov qauv ib txwm muaj ntawm cov protein -synuclein tseem yog qhov kev sib cav tab sis suav tias yog cov protein uas ib txwm muaj nyob rau hauv ib txwm muaj lub cev muaj zog [21,22]. Yog li nws cov qauv tuaj yeem sib txawv raws li kev hloov pauv hauv ib puag ncig hauv zos [23], qhov twg nws tuaj yeem cuam tshuam nrog lipids [24] lossis hlau [25]. Cov kev hloov hauv -synuclein qauv yog xav tias muaj feem xyuam rau nws cov pathological misfolding thiab aggregation feem ntau pom hauv synucleinopathies [26]. Piv txwv li, kev tsim ntawm -synuclein oligomers induced los ntawm kev hloov pauv xws li E35K thiab E57K tau pom tias cuam tshuam rau permeability thiab kev ncaj ncees ntawm cov cell membrane txhawb kev tuag ntawm tes [27]. Txawm hais tias muaj ntau yam tuaj yeem ua rau muaj kev tsis sib haum xeeb -synuclein ntau lawm thiab sib sau ua ke, ib qho ntawm cov koom haum tseem ceeb yog kev hloov pauv ntawm SNCA noob uas encodes -synuclein thiab cov noob no yog thawj qhov kev hloov pauv tau tshaj tawm hauv autosomal-dominant PD [28] nrog tom qab koom nrog DLB [ 8]. Qhov tseeb lub cev muaj nuj nqi ntawm -synuclein tseem tsis tau paub tab sis ntau lub luag haujlwm cuam tshuam nrog kev ua haujlwm synaptic tau raug txheeb xyuas. Cov haujlwm no suav nrog vesicle clustering, rov siv dua, thiab kev saib xyuas ntawm lub pas dej synaptic vesicle reserve [29,30]. Tsis tas li ntawd, -synuclein tau pom los txhawb SNARE complex tsim uas txhim kho cov neurotransmitter tso tawm [31]. Tsis tas li ntawd, nws kuj tseem koom nrog kev tswj hwm kev lag luam hauv lub cev los ntawm kev cuam tshuam nrog ntau tus tswv cuab ntawm Rab GTPase tsev neeg [32], nrog rau microtubule nucleation thiab kev loj hlob tshaj tawm [33]. Lwm cov kev tshawb fawb raws li cov ntaub ntawv los ntawm PD lub hlwb qhia tias -synuclein tuaj yeem tswj hwm qib dopamine los ntawm kev cuam tshuam DAT kev ua haujlwm [34]. Kev nce qib ntawm dopamine tuaj yeem ua rau kev puas tsuaj ntawm tes raws li qhov tshwm sim ntawm oxidative kev nyuaj siab [35]. Tsis ntev los no, -synuclein tau pom tias inhibit phospholipase D (PLD) uas yog lub luag haujlwm rau kev hloov pauv ntawm phosphatidylcholine rau hauv phosphatidic acid, modulating neuronal txheej txheem xws li kev loj hlob, kev sib txawv, thiab kev tso tawm ntawm neurotransmitters thiab DA neurodegeneration [36,37]. -synuclein kuj tau tshaj tawm los ua lub luag haujlwm hauv neuroinflamation los ntawm kev pib lub cev tiv thaiv kab mob. Extracellular -synuclein tuaj yeem ua rau kev ua kom muaj zog thiab kev loj hlob ntawm lub cev tiv thaiv kab mob, cytokine secretion, thiab phagocytosis [38,39].

-synuclein phenotype hauv SNCA-mutated iPSC-derived qauv

iPSCs muaj ntau qhov zoo dua lwm cov qauv, nrog rau kev txwv tsis pub ntawm cov chaw kho mob muaj feem cuam tshuam phenotypic hlwb ntawm tib neeg keeb kwm thaum tswj tus neeg mob tus yam ntxwv genomic qub, suav nrog cov noob hloov pauv lossis chromosome abnormalities. Lub ntsiab SNCA variants txuam nrog cov noob caj noob ces PD suav nrog kev sib tw / kev sib tw [40] thiab kev hloov pauv tsis zoo xws li A53T [41], A30T [42], lossis E46K [9] tau ua qauv hauv iPSCs. Vim tias muaj kev sib kis loj heev lossis A53T SNCA kev hloov pauv hauv PD cov neeg mob, feem coob ntawm iPSC qauv rau hnub no tau tsom mus rau ob hom kev hloov pauv no, thiab lawv cov yam ntxwv phenotypes tau sau tseg hauv daim duab 2.

iPSC qauv ntawm SNCA triplication

SNCA gene multiplication yog txuam nrog lub hnub nyoog yau ntawm PD pib thiab nce cov tsos mob hnyav. Triplications ntawm SNCA tshwm sim nyob rau hauv lub cim ntawm cov ntawv luam ntxiv ntawm SNCA noob thiab overexpression ntawm wildtype -synuclein ua rau tsim cov tshuaj lom aggregates thiab dav neuronal puas [43], tawm tswv yim ib koob tshuaj-nyob ntawm cov nyhuv ntawm -synuclein hauv kab mob ua rau. SNCA cov neeg nqa khoom triplication tam sim no nrog cov phenotype hnyav dua thiab nthuav tawm cov kab mob sai dua li cov neeg nqa khoom sib tw thiab hauv ntau qhov xwm txheej nthuav qhia ntxiv lub cev muaj zog [44]. Kev kuaj mob neuropathological ntawm PD tus neeg mob lub hlwb nrog SNCA triplication qhia tau hais tias muaj kev cuam tshuam loj heev ntawm substantia nigra, zoo kawg li neuronal poob thiab vacuolation nyob rau hauv lub cortex ntawm lub cev, nrog rau kev nthuav dav Lewy lub cev tsub zuj zuj [45]. Qhov no pathology yog mirrored nyob rau hauv iPSC-derived DA neurons nrog SNCA triplication, uas tso saib -synuclein mRNA ntau ntau, uas ua rau txawv txav thiab elevated theem ntawm protein qhia [46]. Tsis tas li ntawd, iPSC-derived neurons harboring qhov kev hloov pauv no qhia ntau dua ntawm -synuclein phosphorylation, ib yam dab tsi uas feem ntau pom hauv PD lub hlwb [47], nrog rau qhov txawv txav ntawm -synuclein aggregates thiab Lewy lub cev [9,48].

iPSC cov qauv tam sim no tseem tab tom pib muab cov ntaub ntawv ntxiv ntawm txoj hauv kev molecular nrog SNCA triplications. Endoplasmic reticulum (ER) kev ntxhov siab thiab kev ua kom lub zog ntawm cov lus teb tsis sib haum (UPR) tau pom tias tau qhib rau hauv iPSC-derived neurons harboring SNCA triplication [49]. Qhov no qhia tau hais tias lub luag haujlwm tseem ceeb ntawm ER ua si hauv kev tshem tawm cov protein ntau tsis sib xws hauv lub xov tooj ntawm tes ua rau ER kev ntxhov siab thiab kev cuam tshuam UPR thaum ER muaj peev xwm tshaj.

Cov txheej txheem neuronal ib txwm raug cuam tshuam los ntawm SNCA triplication thiab iPSC qauv tau pom tias kev sib txawv ntawm cov neuronal thiab kev loj hlob yog hloov los ntawm SNCA triplication. SNCA triplication iPSC-derived neurons tsis tuaj yeem tsim kom muaj kev sib koom ua ke ntawm neuronal, tswj lawv lub peev xwm loj thiab nthuav tawm cov kev hloov pauv hloov pauv hauv kev sib txawv. Cov kev hloov pauv no tau txhawb ntxiv los ntawm qhov kev txo qis tseem ceeb hauv cov noob muaj feem cuam tshuam nrog kev sib txawv xws li DLK, GABABR2, thiab NURR1, thiab qhov txo qis ntawm neurite outgrowth ntev [46,47]. Cov ntaub ntawv no taw qhia txog qhov poob ntawm qhov muaj peev xwm rov ua dua tshiab uas tuaj yeem txuas ntxiv rau cov neeg mob PD.

Txawm hais tias -synuclein feem ntau nyob hauv thaj chaw ntawm cov paj hlwb presynaptic, ib feem me me kuj pom muaj nyob hauv cell nuclei. iPSC neurons nrog SNCA triplication qhia kev hloov pauv hauv genome qauv, ua rau DNA puas [50]. Cov iPSC-derived neurons no qhia txog kev laus phenotypes raws li kev ua pov thawj ntxiv los ntawm kev txo qis ntawm heterochromatin cov cim thiab qhia txog lub hnab ntawv nuclear tsis zoo [48], nrog rau kev cuam tshuam genome kev ncaj ncees inducing DNA strand so thiab cell tuag [50].

Mitochondrial dysfunction yog ib qho kev tshwm sim ntawm neuronal poob thiab yog lub ntsiab organelle cuam tshuam los ntawm -synuclein pathology. Nyob rau hauv txoj kab nrog qhov no, nws yog ib qho uas pom mitochondrial impairment hauv iPSC-derived SNCA triplication neurons [51]. Mitochondrial impairment manifests raws li kev hloov pauv hauv lub zog metabolism vim kev cuam tshuam hauv cov txheej txheem tseem ceeb xws li kev ua pa muaj peev xwm thiab ATP ntau lawm [52]. Thaum SNCA triplication iPSC-derived neurons raug rau qhov tsis tshua muaj siab ntawm calcium ionophore ferritin lossis laser-induced ROS, lawv muaj kev cuam tshuam ntau dua rau permeability hloov pores (PTPs) tsim thaum piv nrog cov tswj neurons [53]. Ntau qhov kev tshawb fawb kuj qhia tau hais tias SNCA kev hloov pauv tau nce basal rhiab heev rau cov tshuaj lom oxidative kev nyuaj siab uas tuaj yeem ua rau hnyav dua los ntawm kev sib cuam tshuam hlau ion [54]. Qhov tshwm sim ntawm SNCA-triplication iPSC-derived neurons rau co toxins xws li 6OHDA ua rau muaj zog cell tuag thiab caspase -3 ua kom [47] nrog rau kev nce hauv autophagosomes [46]. Cov txiaj ntsig no tau txhawb ntxiv los ntawm qib siab ntawm oxidative kev ntxhov siab xws li DNAJA1, HMOX2, UCHL1, thiab HSPB1, koom nrog kev tiv thaiv ntawm tes tiv thaiv oxidative puas tsuaj, thiab MAOA, uas yog ib qho ntawm oxidative kev nyuaj siab thaum overexpressed hauv cov neurons [ 55] ib.

Cistanche ntsiav tshuaj

iPSC qauv ntawm SNCA-A53T kev hloov pauv

iPSC-derived neurons nrog A53T kev hloov pauv pom muaj kev nyiam ntau dua los tsim -synuclein oligomers thiab sib sau ua ke hauv kev sib piv los tswj cov neurons. Qhov no qhia tau zoo nrog qhov pom hauv tib neeg lub hlwb hauv cov neeg mob uas muaj kev hloov pauv tib yam [41,56]. SNCA-A53T kev hloov pauv tsis zoo yog thawj zaug pom thiab yog qhov kev hloov pauv ntau tshaj plaws nyob rau hauv cov neeg mob PD [28]. Qhov kev hloov pauv A53T yog txuam nrog kwv yees li 10- xyoo dhau los ntawm qhov pib pib piv nrog lwm qhov kev hloov pauv tsis zoo [44]. Kev hloov pauv A53T ruaj khov rau -synuclein protein nyob rau hauv -cov ntawv, ua rau muaj qhov nrawm dua ntawm fibril tsim raws li kev ua kom muaj kuab lom, ua rau qhov pib ntxov ntawm tsev neeg PD [26,57]. iPSC-derived neurons kuj qhia dysregulation nyob rau hauv protein ntau lawm thiab transcription-txog mRNAs vim muaj kev cuam tshuam ntawm A53T mutated -synuclein nrog cov tseem ceeb transcription yam, ribonucleoproteins thiab ribosomal proteins, raws li genome-wide tsom xam cov ntaub ntawv [58]. Txawm li cas los xij, lwm txoj kev tshawb fawb tau pom tias qhov txo qis hauv tetramers / monomers piv hauv SNCA-A53T iPSC-derived neurons piv nrog kev tswj qhia tias qee qhov kev hloov pauv xws li tetramers tuaj yeem ua kom cov protein ruaj khov thiab tiv thaiv cov teebmeem tshuaj lom nrog qee cov oligomers [59].

Raws li tau tshaj tawm rau SNCA triplication hauv iPSC-derived neurons, UPR system tseem cuam tshuam hauv SNCA-A53T iPSC-derived neurons. Qhov no yog txuam nrog kev txo qis hauv kev qhia ntawm IRE yam, uas yog ib qho tseem ceeb ntawm cov txheej txheem no [60]. Txoj kev sib raug zoo ntawm lysosomal kev ntxhov siab kuj tseem cuam tshuam rau hauv A53T hloov pauv iPSC-derived neurons, qhov twg -synuclein khi thiab deactivates ykt6, ua rau cov protein sib sau ua ke uas tuaj yeem ua rau muaj mob rau cov neurons [61].

Zoo ib yam li cov qauv dystrophic neurite pom hauv SNCA triplication neurons, qhov no kuj yog cov ntaub ntawv hauv SNCA-A53T iPSC-derived neurons [56]. o varicosities thiab loj spheroid inclusions, uas muaj feem xyuam rau thaum ntxov neurite degeneration muaj nyob rau hauv SNCA-A53T iPSC-derived neurons. Cov kev hloov pauv no ua rau muaj kev cuam tshuam hauv kev tsim cov neuronal tes hauj lwm nrog txo cov synaptic hu [62]. Synaptic kev ua si hauv SNCA-A53T iPSC-derived neurons raug cuam tshuam nrog kev txo qis ntawm qhov tseem ceeb ua ntej thiab postsynaptic cell adhesion proteins pom [62]. Tsis tas li ntawd, qhov tsis zoo ntawm cov txheej txheem no ua rau muaj kev hloov pauv hauv kev ua haujlwm synaptic nrog lub ntsiab lus loj dua ntawm qhov ntau dua ntawm Ca2 ntxiv rau kev hloov pauv [56].

Hauv SNCA-A53T neurons, anterograde mitochondrial thauj txheej txheem cuam tshuam uas zoo li cuam tshuam nrog microtubule nitration thiab tsis muaj peev xwm cuam tshuam nrog mitochondrial thauj complexes [63]. Ib yam li ntawd, SNCA-A53T iPSC-derived neurons qhia mitophagy ncua cuam tshuam nrog kev nce qib ntawm Miro1, cov protein tseem ceeb koom nrog hauv kev thauj mus los mitochondrial [64]. Mitochondrial morphology kuj tau hloov pauv mus rau ntau lub voj voog thiab cov duab tsis zoo nrog kev txo qis hauv nws cov peev xwm hauv cov kab mob sib hloov [60]. Tsis tas li ntawd, txoj hauv kev antioxidant tau nce siab, tej zaum yog lub luag haujlwm them nyiaj hauv kev teb rau qhov nce hauv mitochondrial kev nyuaj siab. Nws tau raug kwv yees tias qhov no yog vim nce qib ntawm catalase lossis peroxisome-proliferator-activated receptor co-activator 1- (PGC1- ) [60]. Tag nrho cov xwm txheej no ua rau muaj kev cuam tshuam rau apoptotic phenotype uas tam sim no nrog SNCA-A53T kev hloov pauv. Muaj kev nce ntxiv ntawm cov proteins uas cuam tshuam nrog autophagy, xws li p62 lossis autophagosome marker LC3 [60]. Cov txheej txheem no tshwj xeeb tshaj yog aggravated nyob rau hauv SNCA-A53T iPSC-derived neurons tom qab raug rau agrochemicals [41].

Lwm yam tseem ceeb cuam tshuam rau -synuclein aggregation thiab pathology pom hauv iPSC qauv

Txawm hais tias muaj kev hloov pauv hauv SNCA yog ib qho tseem ceeb uas txiav txim siab cov protein folding thiab sib sau ua ke rau hauv hom tshuaj lom, lwm yam tseem ceeb thiab qhov sib txawv kuj tau pom los ua lub luag haujlwm hauv cov txheej txheem no. iPSC-derived neurons nrog kev hloov pauv hauv lwm cov noob kuj qhia -synuclein aggregation thiab tso saib cov teebmeem toxicity. iPSC-derived neurons bearing LRRK2 G2019S kev hloov pauv tam sim no nrog nce qib ntawm -synuclein thiab muaj kev sib sau tseem ceeb piv nrog cov tswj [65]. Tsis tas li ntawd, cov neurons no nkag siab rau ntau dhau degeneration thaum raug preformed -synuclein fibrils (PFF). Interestingly, cov nyhuv no tau pom tias yuav thim rov qab, thaum qhov kev hloov pauv tau raug kho hauv isogenic tswj, qhov sib sau ua ke tau txo qis [66]. Tsis tas li ntawd, lwm qhov cuam tshuam rau -synuclein aggregation tau pom vim qhov sib txawv ntawm cov thioredoxin-interacting protein (TXNIP) hauv organoid kab lis kev cai ntawm iPSC-derived neurons nrog LRRK2 G2019S kev hloov. TXNIP tau raug txheeb xyuas yav dhau los tias yog qhov muaj feem pheej hmoo rau PD thiab nws qhov kev hloov pauv thiab qhov sib txawv ntawm qhov qhia tau ua rau nrawm nrawm ntawm -synuclein hauv LRRK2 G2019S neurons [67]. TXNIP kev hloov pauv kuj tseem txuas rau qhov tsis txaus hauv cov txheej txheem autophagy uas ua rau muaj kev nce qib ntawm -synuclein tsub zuj zuj hauv cov neurons [68]. Tag nrho cov ntaub ntawv no kuj pom zoo nrog cov pov thawj los ntawm tib neeg lub hlwb cov qauv, uas qhia tau hais tias nws kim heev -synuclein pathology hauv PD cov neeg mob nrog LRRK2 G2019S kev hloov pauv [69].

Parkin gene (PARK2) encoding E3 ubiquitin ligase yog lwm qhov tseem ceeb hauv iPSC kev tshawb fawb ntawm -synuclein. Cov kev tshawb fawb tsis ntev los no qhia tau hais tias qhov nce siab ntawm -synuclein qib thiab sib sau ua ke hauv iPSC-los ntawm cov neurons los ntawm cov neeg mob uas muaj PARK2 kev hloov pauv piv nrog cov kab tswj [70,71]. Txawm li cas los xij, qhov tsis muaj Lewy lub cev hauv PD cov neeg mob lub hlwb nrog kev hloov pauv hauv qhov chaw ua rau qhov kev sib txuas lus tsis meej, qhia tias parkin nws tus kheej tuaj yeem cuam tshuam thiab ubiquitinate -synuclein-interacting protein, synphilin-1 thiab txhawb nqa Lewy lub cev suav nrog [72] . Kuj tseem muaj pov thawj ntawm cov caj ces tsis tshua muaj kev pheej hmoo rau PD xws li CHCHD2, uas qhia txog kev nce hauv insoluble -synuclein tsub zuj zuj hauv iPSC-derived DA neurons nqa CHCHD2 T61I kev hloov pauv [73].

iPSC cov qauv tshuab tau muaj txiaj ntsig zoo hauv kev ua kom pom cov kev sib txuas no thiab qhia txog cov khoom siv hluav taws xob thiab lub peev xwm uas iPSC thev naus laus zis tuaj yeem coj mus rau cov duab molecular nyuaj ntawm -synuclein neurodegeneration hauv PD.

Cistanche tubulosa

Kev txwv ntawm iPSC qauv ntawm cov qauv kab mob

Txawm hais tias muaj ntau qhov zoo uas iPSC thev naus laus zis pab txhawb kev ua qauv kab mob, tseem muaj qee qhov kev txwv thiab kev sib tw kom kov yeej. Ua ntej, qhov kev sib tw ntau tshaj plaws yog cov qog nqaij hlav uas yuav raug ntxias thaum lub sij hawm reprogramming txheej txheem siv retroviral thiab lentiviral reprogramming txoj kev. Qhov tsis paub lossis tsis ntsuas qhov cuam tshuam ntawm cov txheej txheem reprogramming yog qhov muaj peev xwm tsis txaus ntseeg hauv kev ntsuam xyuas tus neeg sawv cev tiag tiag ntawm iPSCs raws li cov qauv kab mob tshwj xeeb. Txawm li cas los xij, nws yuav tsum raug sau tseg tias cov txheej txheem tsis ntev los no siv txoj hauv kev tsis muaj kev sib koom ua ke xws li Sendai tus kab mob lossis DNA vectors thiab mus qee txoj hauv kev los txo cov teeb meem no [74,75]. Lwm qhov teeb meem uas paub zoo nrog cov kev tshawb fawb qia cell yog qhov sib txawv ntawm cov iPSCs tsim los ntawm cov neeg pub dawb sib txawv, lossis cov clones los ntawm tib tus neeg pub dawb, qhov kev hloov pauv no nyuaj rau kev sib haum xeeb hauv qee qhov xwm txheej vim tias nws yuav ua rau tus neeg mob muaj txiaj ntsig lossis kev ua raws cai. Reprogramming yog tsim los ua kom rov ua tiav cov ntiv tes epigenetic ntawm tus pub lub hlwb uas ua rau muaj peev xwm ua rau muaj kev sib txawv ntawm qhov muaj peev xwm rau qee yam ntawm tes [76], txawm li cas los xij, qee cov ntaub ntawv tshwm sim qhia tias epigenetic nco ploj zuj zus nyob rau lub sijhawm hauv kab lis kev cai [77] . Ib qho ntawm cov kev txwv tseem ceeb ntawm iPSCs hauv PD qauv yog tsim DA neurons nrog kev laus phenotype. Cov kev tshawb fawb tau pom tias cov txheej txheem reprogramming rov pib dua lub hnub nyoog cell mus rau lub xeev hluas dua, nrog cov phenotypes muaj telomeres ntev, txo oxidative kev nyuaj siab, thiab muaj peev xwm mitochondrial lub koom haum [78,79]. Feem ntau txhua lub hlwb siv ntau yam kev tswj xyuas zoo los tiv thaiv kev ua haujlwm ntawm lub cev, yog li nws muaj peev xwm hais tias phenotypic tsis xws luag tsuas yog tshwm sim thaum txoj kev tiv thaiv tawg. Yog li tsim kom muaj hnub nyoog phenotype yog ib txoj haujlwm nyuaj tab sis qee cov ntaub ntawv tsis ntev los no qhia tias muaj peev xwm ua rau muaj hnub nyoog phenotype los ntawm kev sib ntxiv ntawm progerin ib daim ntawv luv luv ntawm lamin A uas cuam tshuam nrog kev laus ntxov ntxov [80], thiab telomerase inhibition [81]. Muaj qee qhov teeb meem thaum siv iPSC-derived neurons los ua qauv kab mob thiab tshwj xeeb tshaj yog cov kab mob hnub nyoog. Txawm hais tias muaj kev sib tw thiab muaj peev xwm pitfalls, iPSC-derived neurons yog ib qho tseem ceeb hauv kev ua qauv -synuclein pathology.

Cov lus qhia yav tom ntej nrog iPSC qauv ntawm -synuclein pathology

iPSC-derived neurons tso cai rau peb los tsim 'kab mob hauv ib lub tais' tab sis kuj pab txhawb kev kawm ntxaws txog cov kab mob hauv lub cev hauv lub cev hauv vitro. -synuclein aggregated hom muaj nyob rau hauv lub hlwb ntawm feem ntau lub hlwb PD cov neeg mob thiab iPSCs yog ib tug haib cuab tam los kawm txog kev sib raug zoo ntawm -synuclein thiab neurodegeneration, tshawb txog lub physiological thiab pathophysiological luag hauj lwm ntawm -synuclein. Cov ntaub ntawv los ntawm neuronal iPSC-los ntawm cov qauv ntawm cov kev hloov pauv caj ces cuam tshuam nrog PD yog loj hlob thiab qhia muaj kev sib raug zoo nrog cov ntaub ntawv los ntawm tib neeg lub hlwb kuaj [9]. Tshwj xeeb, nyob rau hauv rooj plaub ntawm SNCA kev hloov pauv uas muaj nyob rau hauv cov pej xeem PD, nws yog ib qho tseem ceeb uas iPSCs ua tus qauv tuaj yeem rov hais dua cov kab mob hauv lub xeev. Cov ntaub ntawv tshuaj xyuas no qhia tias iPSCs yog ib qho qauv zoo heev los kawm txog lub cev thiab kab mob ntawm SNCA kev hloov pauv.

Feem ntau, SNCA kev hloov pauv ua rau muaj kev ruaj khov thiab sib sau ua ke lossis fibrillation ntawm -synuclein hauv Lewy lub cev ua ke nrog lwm cov proteins. Thaum cov kab mob sib sau ua ke no muaj nyob hauv lub xov tooj ntawm tes, lawv cuam tshuam nrog lwm cov qauv ntawm tes xws li microtubules, cuam tshuam kev thauj mus los ntawm axonal mitochondrial thiab thaum kawg ua rau muaj kev cuam tshuam ntawm cov synaptic terminals thiab cell poob [9,26]. Tsis tas li ntawd, cov haujlwm tseem ceeb mitochondrial cuam tshuam los ntawm -synuclein oligomers 'kev cuam tshuam nrog ATP synthases xws li qhib PTPs, ua tsis taus pa, thiab lipid peroxidation induction [53]. Ntxiv mus, -synuclein aggregates 'kev cuam tshuam nrog cov proteins koom nrog hauv mitophagy, thiab tiv thaiv qhov tsim nyog tshem tawm ntawm mitochondria tsis zoo los ntawm hauv lub cell [64]. Kev sib cuam tshuam ntawm -synuclein oligomers nrog hlau ions kuj tau pom zoo kom tsim cov dawb radicals hauv cov neurons, ua rau muaj kev cuam tshuam ntawm cov cell physiology, ua rau cell tuag [54]. Feem ntau ntawm cov phenotypes tso tawm los ntawm iPSC-derived neurons kuj pom nyob rau hauv tib neeg lub hlwb, qhia txog qhov tsim nyog ntawm iPSC qauv tsis yog tsuas yog ua raws li lub cev ntawm lub cev thiab kab mob tab sis kuj lawv lub luag haujlwm tseem ceeb ua lub platform los nthuav tawm cov ntaub ntawv tshiab uas yuav muaj yav tas los. tso siab rau kev sau cov hlwb biopsies los ntawm cov neeg mob tuag.

Kab mob ua qauv nrog iPSCs tau muab cov pov thawj tseem ceeb uas cuam tshuam rau lwm cov txheej txheem ntawm tes tuaj yeem ua rau muaj kev cuam tshuam -synuclein aggregation thiab tsub zuj zuj. iPSC-derived neurons los ntawm PD cov neeg mob uas muaj kev hloov pauv, hauv LRRK2 lossis parkin qhia txog cov kev cuam tshuam no. Piv txwv li, ubiquitination ntawm synphilin-1 hauv iPSC-derived neurons bearing parkin mutations yog pom zoo kom muaj lub luag haujlwm nruab nrab hauv inducing Lewy lub cev tsim [72]. Tsis tas li ntawd, ib qho ntawm cov txheej txheem tseem ceeb uas ua rau -synuclein tsub zuj zuj yog qhov tsis xws luag autophagy thiab lysosomal proteolysis, uas ua lub luag haujlwm tseem ceeb hauv kev tshem tawm cov khoom tsis zoo. Cov txheej txheem no tau pom tias muaj kev cuam tshuam hauv LRRK2-mutated iPSC-derived neurons [68,82]. Hauv tag nrho cov kev tshawb fawb no, iPSC-derived neurons qhia phenotypes uas zoo sib xws nrog cov ntawv tshaj tawm rau tib neeg lub hlwb kuaj. Kev ntsuam xyuas qhov ua rau -synuclein aggregates feem ntau pom hauv PD lub hlwb yog qhov nyuaj thiab rau hnub tim tau ua pov thawj tsis tiav.

Herba Cistanche

Thaum lub luag haujlwm tseem ceeb ntawm -synuclein aggregation hauv PD pathology tseem tsis tau meej meej, cov ntaub ntawv qhia tau hais tias muaj kev cuam tshuam loj heev ntawm cov kab mob sib sau ua ke nrog ntau lwm cov proteins hauv lub xov tooj ntawm tes, tsim kom muaj kev cuam tshuam ntawm cellular txoj kev puas tsuaj uas ua rau muaj qhov tsis zoo ntawm cov protein sib sau ua ke, thaum kawg ua rau. degeneration. Hauv qhov dav thiab qhov sib txawv ntawm cov toj roob hauv pes molecular no, iPSC-ua qauv los ntawm cov neeg mob PD tuaj yeem pab txheeb xyuas cov txiaj ntsig ntawm kev hloov pauv ntau tshaj plaws hauv cov kab mob no, tuaj yeem ua raws li cov txheej txheem ntawm tes ntawm PD lub hlwb nrog qhov tseeb. Ntxiv mus, qhov no 'kab mob nyob rau hauv ib lub tais' qauv qauv tuaj yeem pab txhawb ob qho tib si kev tshawb nrhiav tshuaj thiab kev tshawb fawb txog kev kho cellular. Kev ua haujlwm yav tom ntej nrog CRISPR-Cas9 thev naus laus zis ua ke nrog iPSCs tuaj yeem hloov kho txoj hauv kev rau synucleinopathies los hloov cov kev hloov pauv tsis zoo lossis tshem tawm qhov sib npaug ntawm cov kab mob tseem ceeb [83] lossis qhov tseeb kev hloov kho ntawm cov txheej txheem cuam tshuam xws li histones koom nrog kev hloov pauv tom qab [ 84] ib.

Kev ua haujlwm dav dav ua rau niaj hnub hla ntau lub qauv qauv, qhia tau hais tias muaj cov -synuclein aggregates, oligomers, thiab fibrils muaj lub luag haujlwm tseem ceeb hauv PD-txog DA neurodegeneration. Nrog rau kev txhim kho kab mob cuam tshuam nrog lub hauv paus siv iPSCs thiab kev loj hlob sai hauv peb txoj kev nkag siab ntawm lub xeev tus kab mob, lub neej yav tom ntej zoo li ci ntsa iab rau cov kev kho mob uas tuaj yeem tsom mus rau synucleinopathies.

Cov ntaub ntawv

1. Tsuiji, H. thiab Yamanaka, K. (2014) Tsiaj qauv rau cov kab mob neurodegenerative. Tsiaj Biotechnology, pp. 39–56, Elsevier,

2. Bourdenx, M., Koulakiotis, NS, Sanoudou, D., Bezard, E., Dehay, B. and Tsarbopoulos, A. (2017) Protein aggregation and neurodegeneration in prototypical neurodegenerative disease: piv txwv ntawm amyloidopathies, tauopathies, thiab synucles . Prog. Neurobiol. 155, 171–193, ib.

3. Madabhushi, R., Pan, L. and Tsai, L.-H. (2014) DNA puas thiab nws txuas rau neurodegeneration. Neuron 83, 266–282, ib.

4. Rekatsina, M., Paladini, A., Piroli, A., Zis, P., Pergolizzi, JV and Varrassi, G. (2020) Pathophysiology and therapeutic perspectives of oxidative stress and neurodegenerative diseases: a narrative review. Adv. Ther. 37, 113–139, NW.

5. Kovacs, GG (2016) Molecular pathological kev faib tawm ntawm cov kab mob neurodegenerative: tig mus rau cov tshuaj precision. Int. J. Mol. Sci. 17,

6. Kovacs, GG (2017) Lub tswv yim thiab kev faib tawm ntawm cov kab mob neurodegenerative. Handb. Clin. Neurol. 145, 301–307, ib.

7. Kiely, AP, Asi, YT, Kara, E., Limousin, P., Ling, H., Lewis, P., et al. (2013) -Synucleinopathy cuam tshuam nrog G51D SNCA kev hloov pauv: kev sib txuas ntawm Parkinson tus kab mob thiab ntau yam kab mob atrophy? Acta Neuropathol. 125, 753–769, ib.

8. Zarranz, JJ, Alegre, J., G'omez-Esteban, JC, Lezcano, E., Ros, R., Ampuero, I. et al. (2004) Qhov kev hloov tshiab, E46K, ntawm alpha-synuclein ua rau Parkinson thiab Lewy lub cev dementia. Ann. Neurol. 55, 164–173, ib.

9. Prots, I., Grosch, J., Brazdis, R.-M., Simmnacher, K., Veber, V., Havlicek, S. et al. (2018) -Synuclein oligomers induce ntxov axonal dysfunction nyob rau hauv tib neeg iPSC-raws li qauv ntawm synucleinopathies. Proc. Natl. Acad. Sci. USA 115, 7813–7818,

10. McCann, H., Stevens, CH, Cartwright, H. and Halliday, GM (2014) -Synucleinopathy phenotypes. Parkinsonism Relat. Teeb meem. 20, S62–S67, HWV.

11. Takahashi, K., Tanabe, K., Ohnuki, M., Narita, M., Ichisaka, T., Tomoda, K. et al. (2007) Induction ntawm pluripotent qia hlwb los ntawm cov neeg laus neeg fibroblasts los ntawm cov ntsiab lus txhais. Cell 131, 861–872,

12. Vogel, G. (2010) Stem cells. Kab mob nyob rau hauv ib lub tais tshem tawm. Kev Tshawb Fawb 330, 1172–1173,

13. Avazzadeh, S., Baena, JM, Keighron, C., Feller-Sanchez, Y. and Quinlan, LR (2021) Modeling Parkinson's disease: iPSCs rau kev nkag siab zoo ntawm tib neeg pathology. Lub hlwb Sci. 11,

14. S´anchez-Dan'es, A., Consiglio, A., Richaud, Y., Rodr´ıguez-Piz`a, I., Dehay, B., Edel, M., et al. (2012) Ua tau zoo tiam ntawm A9 midbrain dopaminergic neurons los ntawm lentiviral xa ntawm LMX1A hauv tib neeg embryonic qia hlwb thiab induced pluripotent qia hlwb. Hum. Gene Ther. 23, 56–69 : kuv.

15. Chambers, SM, Fasano, CA, Papapetrou, EP, Tomishima, M., Sadelain, M. and Studer, L. (2009) Muaj txiaj ntsig zoo ntawm kev hloov dua siab tshiab ntawm tib neeg ES thiab iPS hlwb los ntawm dual inhibition ntawm SMAD signaling. Nat. Biotechnol. 27, 275–280, ib.

16. Kriks, S., Shim, J.-W., Piao, J., Ganat, YM, Wakeman, DR, Xie, Z. et al. (2011) Dopamine neurons muab los ntawm tib neeg ES hlwb ua tau zoo hauv cov qauv tsiaj ntawm Parkinson tus kab mob. Xwm Txheej 480, 547–551,

17. Theka, I., Caiazzo, M., Dvoretskova, E., Leo, D., Ungaro, F., Curreli, S. et al. (2013) Kev tsim sai sai ntawm kev ua haujlwm dopaminergic neurons los ntawm tib neeg induced pluripotent qia hlwb los ntawm cov txheej txheem ib-kauj ruam uas siv cov kab mob ntawm cov kab mob sib kis. Stem Cells Transl. Med. 2, 473–479 : kuv.

18. Wang, M., Ling, K. H., Tan, JJ and Lu, C. B. (2020) Kev loj hlob thiab kev sib txawv ntawm midbrain dopaminergic neuron: los ntawm lub rooj ntev zaum mus rau hauv txaj. Cells 9,

19. Marton, RM thiab Ioannidis, JPA (2019) Kev tshuaj xyuas dav dav ntawm cov txheej txheem rau muab cov dopaminergic neurons los ntawm tib neeg pluripotent qia hlwb. Stem Cells Transl. Med. 8, 366–374, ib.

20. Maroteaux, L., Campanelli, JT thiab Scheller, RH (1988) Synuclein: ib tug neuron-specific protein nyob rau hauv lub nucleus thiab presynaptic paj terminal. J. Neeb. 8, 2804–2815, ib.

21. Uversky, VN, Li, J. thiab Fink, AL (2001) Cov pov thawj rau ib feem folded intermediate nyob rau hauv alpha-synuclein fibril tsim. J. Biol. Chem. 276, 10737–10744, ib.

22. Theillet, F.-X., Binolfifi, A., Bekei, B., Martorana, A., Rose, HM, Stuiver, M. et al. (2016) Cov qauv kev tsis sib haum xeeb ntawm monomeric -synuclein tseem nyob hauv cov hlwb mammalian. Xwm Txheej 530, 45–50,

23. Buell, AK, Galvagnion, C., Gaspar, R., Sparr, E., Vendruscolo, M., Knowles, TPJ et al. (2014) Kev daws teeb meem txiav txim siab qhov tseem ceeb ntawm nucleation thiab kev loj hlob hauv -synuclein aggregation. Proc. Natl. Acad. Sci. USA 111, 7671–7676,

24. Rovere, M., Sanderson, JB, Fonseca-Ornelas, L., Patel, DS thiab Bartels, T. (2018) Refolding ntawm helical soluble -synuclein los ntawm kev cuam tshuam nrog lipid interfaces. PEB Lett. 592, 1464–1472, ib.

25. Moons, R., Konijnenberg, A., Mensch, C., Van Elzen, R., Johannessen, C., Maudsley, S. et al. (2020) Hlau ions zoo li-synuclein. Sci. Rep. 10, 16293, ib.

26. Bertoncini, CW, Fernandez, CO, Griesinger, C., Jovin, TM thiab Zweckstetter, M. (2005) Tsev neeg mutants ntawm alpha-synuclein nrog nce neurotoxicity muaj ib tug destabilized conformation. J. Biol. Chem. 280, 30649–30652, ib.

27. Winner, B., Jappelli, R., Maji, SK, Desplats, PA, Boyer, L., Aigner, S. et al. (2011) Hauv vivo ua qauv qhia tias alpha-synuclein oligomers yog tshuaj lom. Proc. Natl. Acad. Sci. USA 108, 4194–4199,

28. Polymeropoulos, MH, Lavedan, C., Leroy, E., Ide, SE, Dehejia, A., Dutra, A. et al. (1997) Kev hloov pauv hauv cov noob alpha-synuclein txheeb xyuas hauv cov tsev neeg uas muaj tus kab mob Parkinson. Kev Tshawb Fawb 276, 2045–2047,

29. Lashuel, HA, Overk, CR, Oueslati, A. and Masliah, E. (2013) Lub ntsej muag ntau ntawm -synuclein: los ntawm cov qauv thiab toxicity rau cov hom phiaj kho. Nat. Rev. Neurosci. 14, 38–48, IB.

30. Cabin, DE, Shimazu, K., Murphy, D., Cole, NB, Gottschalk, W., McIlwain, KL et al. (2002) Synaptic vesicle depletion correlates nrog attenuated synaptic cov lus teb rau lub sij hawm repetitive stimulation nyob rau hauv nas tsis muaj alpha-synuclein. J. Neeb. 22, 8797–8807, ib.

31. Burr'e, J., Sharma, M., Tsetsenis, T., Buchman, V., Etherton, MR and S ¨udhof, TC (2010) Alpha-synuclein txhawb nqa SNARE-complex sib dhos hauv vivo thiab hauv vitro. Kev Tshawb Fawb 329, 1663–1667,

32. Miraglia, F., Ricci, A., Rota, L. thiab Colla, E. (2018) Subcellular localization ntawm alpha-synuclein aggregates thiab lawv cov kev cuam tshuam nrog daim nyias nyias. Neural Regen. Res. 13, 1136–1144, ib.

33. Carnwath, T., Mohammed, R. and Tsiang, D. (2018) The direct and indirect effects of -synuclein on microtubule stability in the pathogenesis of Parkinson's disease. Neuropsychiatr. Dis. Kho. 14, 1685–1695, ib.

34. Wersinger, C. and Sidhu, A. (2003) Attenuation of dopamine transporter activation by -synuclein. Neurosci. Lett. 340, 189–192, ib.

35. Lee, FJ, Liu, F., Pristupa, ZB thiab Niznik, HB (2001) Kev khi ncaj qha thiab kev ua haujlwm sib txuas ntawm alpha-synuclein rau cov dopamine transporters accelerate dopamine-induced apoptosis. FASEB J. 15, 916–926

36. Ahn, B.H., Rhim, H., Kim, S., Sung, Y.M., Lee, M.Y., Choi, J.Y. ua al. (2002) alpha-Synuclein cuam tshuam nrog phospholipase D isozymes thiab inhibits pervanadate-induced phospholipase D activation hauv tib neeg lub raum embryonic -293 hlwb. J. Biol. Chem. 277, 12334–12342, ib.

37. Gorbatyuk, OS, Li, S., Nguyen, FN, Manfredsson, FP, Kondrikova, G., Sullivan, LF et al. (2010) -Synuclein qhia hauv nas substantia nigra suppresses phospholipase D2 toxicity thiab nigral neurodegeneration. Mol. Ther. 18, 1758–1768, ib.

38. Ferreira, SA thiab Romero-Ramos, M. (2018) Microglia teb thaum tus kab mob Parkinson: alpha-synuclein cuam tshuam. Pem hauv ntej. Cell. Neurosci. 12, 247, ib.

39. Grozdanov, V. and Danzer, KM (2020) Intracellular alpha-synuclein and immune cell function. Pem hauv ntej. Cell Dev. Biol. 8, 562692, ib.

40. Devine, MJ, Ryten, M., Vodicka, P., Thomson, AJ, Burdon, T., Houlden, H. et al. (2011) Parkinson tus kab mob induced pluripotent qia hlwb nrog triplication ntawm -synuclein locus. Nat. Pawg. 2, 440, ib.

41. Ryan, SD, Dolatabadi, N., Chan, SF, Zhang, X., Akhtar, MW, Parker, J. et al. (2013) Isogenic human iPSC Parkinson tus qauv qhia tau hais tias nitrosative stress-induced dysfunction hauv MEF2-PGC1 transcription. Cell 155, 1351–1364,

42. Barbuti, P., Antony, P., Santos, B., Massart, F., Cruciani, G., Dording, C. et al. (2020) Siv cov ntsiab lus tshuaj ntsuam xyuas los tsim ib leeg-cell noob-kho tus neeg mob-los ntawm iPS clones qhia ntau tshaj alpha-synuclein nrog tsev neeg Parkinson tus kab mob taw tes hloov pauv A30P. Cells 9,

43. Deng, H. and Yuan, L. (2014) Genetic variants and animal model in SNCA and Parkinson's disease. Kev laus Res. Tshwmsim 15, 161–176,

44. Kasten, M. thiab Klein, C. (2013) Muaj ntau lub ntsej muag ntawm alpha-synuclein hloov pauv. Mon. Teeb meem. 28, 697–701, ib.

45. Singleton, AB, Farrer, M., Johnson, J., Singleton, A., Hague, S., Kachergus, J. et al. (2003) alpha-Synuclein locus triplication ua rau Parkinson tus kab mob. Kev tshawb fawb 302, 841,

46. ​​Oliveira, LMA, Falomir-Lockhart, LJ, Botelho, MG, Lin, KH, Wales, P., Koch, JC et al. (2015) Elevated -synuclein tshwm sim los ntawm SNCA noob triplication impairs neuronal sib txawv thiab maturation nyob rau hauv Parkinson tus neeg mob-derived induced pluripotent qia hlwb. Cell Tuag Dis. Peb 6, 1994

47. Lin, L., G¨oke, J., Cukuroglu, E., Dranias, MR, VanDongen, AMJ and Stanton, LW (2016) Molecular features underlying neurodegeneration identified through in vitro modeling of genetic diverse Parkinson's disease. Cell Rep. 15, 2411–2426,

48. Tagliafifierro, L., Zamora, ME thiab Chiba-Falek, O. (2019) Kev sib faib ntawm SNCA locus exacerbates neuronal nuclear aging. Hum. Mol. Genet. 28, 407–421, ib.

49. Heman-Ackah, SM, Manzano, R., Hoozemans, JJM, Scheper, W., Flynn, R., Hagerty, W. et al. (2017) Alpha-synuclein induces unfolded protein teb nyob rau hauv Parkinson tus kab mob SNCA triplication iPSC-derived neurons. Hum. Mol. Genet. 26, 4441–4450, ib.

50. Vasquez, V., Mitra, J., Hegde, PM, Pandey, A., Sengupta, S., Mitra, S., et al. (2017) Chromatin-bound oxidized -synuclein ua rau strand so hauv neuronal genomes hauv vitro qauv ntawm Parkinson tus kab mob. J. Alzheimer's Dis. 60, S133–S150,

51. Brazdis, R.-M., Alecu, JE, Marsch, D., Dahms, A., Simmnacher, K., L ¨orentz, S. et al. (2020) Ua qauv qhia ntawm lub hlwb thaj tsam tshwj xeeb neuronal vulnerability nyob rau hauv tib neeg iPSC-raws li qauv ntawm tsev neeg Parkinson tus kab mob. Hum. Mol. Genet. 29, 1180–1191, ib.

52. Flierl, A., Oliveira, LMA, Falomir-Lockhart, LJ, Mak, SK, Hesley, J., Soldner, F. et al. (2014) Cov kev pheej hmoo siab dua thiab kev ntxhov siab ntawm cov hlwb neuronal precursor nqa ib qho alpha-synuclein noob triplication. PLoS ONE 9, e112413,

53. Ludtmann, MHR, Angelova, PR, Horrocks, MH, Choi, ML, Rodrigues, M., Baev, AY et al. (2018) -synuclein oligomers cuam tshuam nrog ATP synthase thiab qhib lub permeability hloov pore hauv Parkinson tus kab mob. Nat Commun. 9, 2293, ib.

54. Deas, E., Cremades, N., Angelova, PR, Ludtmann, MHR, Yao, Z., Chen, S. et al. (2016) Alpha-synuclein oligomers cuam tshuam nrog cov hlau ions kom ua rau oxidative kev nyuaj siab thiab neuronal tuag hauv Parkinson tus kab mob. Antioxidant. Redox teeb liab. 24, 376–391, ib.

55. Byers, B., Cord, B., Nguyen, HN, Sch ¨ule, B., Fenno, L., Lee, PC et al. (2011) SNCA triplication Parkinson tus neeg mob tus iPSC-derived DA neurons sau -synuclein thiab muaj kev cuam tshuam rau oxidative kev nyuaj siab. PLoS ONE 6, e26159,

56. Zygogianni, O., Antoniou, N., Kalomoiri, M., Kouroupi, G., Taoufifik, E. and Matsas, R. (2019) Hauv vivo phenotyping ntawm tsev neeg Parkinson tus kab mob nrog tib neeg induced pluripotent qia hlwb: ib qho pov thawj -txoj kev kawm. Neurochem. Res. 44, 1475–1493, ib.

57. Conway, KA, Harper, JD thiab Lansbury, PT (1998) Accelerated in vitro fibril formation by a mutant alpha-synuclein linked to Early-onset Parkinson disease. Nat. Med. 4, 1318–1320, ib.

58. Khurana, V., Peng, J., Chung, CY, Auluck, PK, Fanning, S., Tardiff, DF et al. (2017) Genome-scale tes hauj lwm txuas cov kab mob neurodegenerative noob rau -synuclein los ntawm txoj hauv kev tshwj xeeb. Cell Syst. 4, 157.e14–170.e14,

59. Dettmer, U., Newman, AJ, Soldner, F., Luth, ES, Kim, NC, von Saucken, VE et al. (2015) Parkinson-ua rau -synuclein missense mutations hloov cov neeg tetramers rau monomers raws li ib tug mechanism rau kab mob pib. Nat. Pawg. 6, 7314 ib.

60. Zambon, F., Cherubini, M., Fernandes, HJR, Lang, C., Ryan, BJ, Volpato, V. et al. (2019) Cellular -synuclein pathology yog txuam nrog bioenergetic dysfunction nyob rau hauv Parkinson's iPSC-derived dopamine neurons. Hum. Mol. Genet. 28, 2001–2013,

61. Cuddy, LK, Wani, WY, Morella, ML, Pitcairn, C., Tsutsumi, K., Fredriksen, K. et al. (2019) Kev ntxhov siab-vim cellular clearance yog kho los ntawm SNARE protein ykt6 thiab cuam tshuam los ntawm -synuclein. Neuron 104, 869.e11–884.e11,

62. Kouroupi, G., Taoufifik, E., Vlachos, IS, Tsioras, K., Antoniou, N., Papastefanaki, F. et al. (2017) Kev sib txuas ntawm cov synaptic thiab axonal neuropathology hauv tib neeg iPSC-raws li qauv ntawm tsev neeg Parkinson tus kab mob. Proc. Natl. Acad. Sci. USA 114, E3679–E3688,

63. Stykel, MG, Humphries, K., Kirby, MP, Czaniecki, C., Wang, T., Ryan, T. et al. (2018) Nitration ntawm microtubules thaiv axonal mitochondrial thauj hauv tib neeg pluripotent qia cell qauv ntawm Parkinson tus kab mob. FASEB J. 32, 5350–5364,

64. Shaltouki, A., Hsieh, C.-H., Kim, MJ thiab Wang, X. (2018) Alpha-synuclein qeeb mitophagy thiab tsom Miro cawm neuron poob hauv Parkinson tus qauv. Acta Neuropathol. 136, 607–620, ib.

65. Nguyen, HN, Byers, B., Cord, B., Shcheglovitov, A., Byrne, J., Gujar, P. et al. (2011) LRRK2 mutant iPSC-derived DA neurons qhia tau tias muaj kev cuam tshuam rau oxidative kev nyuaj siab. Cell Stem Cell 8, 267–280,

66. Bieri, G., Brahic, M., Bousset, L., Couthouis, J., Kramer, NJ, Ma, R. et al. (2019) LRRK2 hloov kho -syn pathology thiab kis hauv nas qauv thiab tib neeg neurons. Acta Neuropathol. 137, 961–980, ib.

67. Kim, H., Park, J., Choi, H., Chang, H., Park, H., Shin, J. et al. (2019) Modeling G2019S-LRRK2 sporadic Parkinson's disease nyob rau hauv 3D midbrain organoids. Stem Cell Rep. 12, 518–531,

68. Reinhardt, P., Schmid, B., Burbulla, LF, Sch ¨ondorf, DC, Wagner, L., Glatza, M. et al. (2013) Kev kho noob caj noob ces ntawm LRRK2 kev hloov pauv hauv tib neeg iPSCs txuas nrog Parkinsonian neurodegeneration rau ERK-raws li kev hloov pauv hauv cov noob qhia. Cell Stem Cell. 12, 354–367, ib.

69. Schiesling, C., Kieper, N., Seidel, K. and Kr¨uger, R. (2008) Review: Familial Parkinson's disease–genetics, clinical phenotype and neuropathology about the common sporadic form of the disease. Neuropathol. Appl. Neurobiol. 34, 255–271, ib.

70. Shaltouki, A., Sivapatham, R., Pei, Y., Gerencser, AA, Momˇcilovi ´c, O., Rao, MS et al. (2015) Mitochondrial alterations los ntawm PARKIN hauv dopaminergic neurons siv PARK2 tus neeg mob tshwj xeeb thiab PARK2 knockout isogenic iPSC kab. Stem Cell Rep. 4, 847–859,

71. Imaizumi, Y., Okada, Y., Akamatsu, W., Koike, M., Kuzumaki, N., Hayakawa, H. et al. (2012) Mitochondrial dysfunction txuam nrog nce oxidative kev nyuaj siab thiab -synuclein tsub zuj zuj nyob rau hauv PARK2 iPSC-derived neurons thiab postmortem hlwb ntaub so ntswg. Mol. Lub hlwb 5, 35,

72. Chung, KK, Zhang, Y., Lim, KL, Tanaka, Y., Huang, H., Gao, J., et al. (2001) Parkin ubiquitinates alpha-synuclein-interacting protein, synphilin-1: cuam tshuam rau Lewy-lub cev tsim hauv tus kab mob Parkinson. Nat. Med. 7, 1144–1150, ib.

73. Ikeda, A., Nishioka, K., Meng, H., Takanashi, M., Hasegawa, I., Inoshita, T. et al. (2019) Kev hloov pauv hauv CHCHD2 ua rau -synuclein aggregation. Hum. Mol. Genet. 28, 3895–3911, ib.

74. Papapetrou, EP thiab Sadelain, M. (2011) Generation of transgene-free human induced pluripotent stem cells with an excisable single polycistronic vector. Nat. Protoc. 6, 1251–1273, ib.

75. Narsinh, KH, Jia, F., Robbins, RC, Kay, MA, Longaker, MT and Wu, JC (2011) Generation of adult human induced pluripotent stem cells using nonviral minicircle DNA vectors. Nat. Protoc. 6, 78–88, ib.

76. Kim, K., Zhao, R., Doi, A., Ng, K., Unternahrer, J., Cahan, P. et al. (2011) Hom pub dawb tuaj yeem cuam tshuam cov epigenome thiab qhov sib txawv ntawm tib neeg induced pluripotent qia hlwb. Nat. Biotechnol. 29, 1117–1119, ib.

77. Nishino, K., Toyoda, M., Yamazaki-Inoue, M., Fukawatase, Y., Chikazawa, E., Sakaguchi, H. et al. (2011) DNA methylation dynamics nyob rau hauv tib neeg induced pluripotent qia hlwb dhau sij hawm. PLoS Genet. 7, e1002085,

78. Yehezkel, S., Rebibo-Sabbah, A., Segev, Y., Zuckerman, M., Shaked, R., Huber, I. et al. (2011) Reprogramming ntawm telomeric cheeb tsam thaum lub sij hawm tiam ntawm tib neeg induced pluripotent qia hlwb thiab tom qab sib txawv rau hauv fibroblast zoo li derivatives. Epigenetics 6, 63–75,

79. Rohani, L., Johnson, AA, Arnold, A. and Stolzing, A. (2014) Lub hnub nyoog kos npe: lub cim ntawm induced pluripotent qia hlwb? Hnub nyoog Cell 13, 2–7,

80. Miller, JD, Ganat, YM, Kishinevsky, S., Bowman, RL, Liu, B., Tu, EY et al. (2013) Tib neeg iPSC-raws li tus qauv ntawm tus kab mob lig-pib los ntawm progerin-induced aging. Cell Stem Cell 13, 691–705,

81. Vera, E., Bosco, N. and Studer, L. (2016) Generating late-onset human iPSC-based disease model by inducing neuronal age-related phenotypes through telomerase manipulation. Cell Rep. 17, 1184–1192,

82. S'anchez-Dan'es, A., Richaud-Patin, Y., Carballo-Carbajal, I., Jim'enez-Delgado, S., Craig, C., Mora, S., et al. (2012) Kab mob tshwj xeeb phenotypes hauv dopamine neurons los ntawm tib neeg iPS-raws li qauv ntawm cov caj ces thiab cov kab mob Parkinson tsis sib xws. EMBO MOL. Med. 4, 380–395 : kuv.

83. Safari, F., Hatam, G., Behbahani, AB, Rezaei, V., Barekati-Mowahed, M., Petramfar, P. et al. (2020) CRISPR system: ib lub thawv siab tshaj plaws rau kev tshawb fawb thiab kho tus kab mob Parkinson. Cell. Mol. Neurobiol. 40, 477–493, ib

84. Guhathakurta, S., Kim, J., Adams, L., Basu, S., Song, MK, Adler, E. et al. (2021) Target attenuation of elevated histone marks at SNCA alleviates -synuclein in Parkinson's disease. EMBO MOL. Med. 13 Ib., 12188.

Jara M. Baena-Montes1, Sahar Avazzadeh1 thiab Leo R. Quinlan1,2

1. Physiology School of Medicine, National University of Ireland Galway, Galway, Ireland;

2. C ´ URAM SFI Center rau Kev Tshawb Fawb Txog Kev Kho Mob, National University of Ireland Galway, Galway, Ireland