Methylation Raws li Tus Txheej Txheem Tseem Ceeb Ntawm Tau Aggregation Thiab Neuronal Health hauv Alzheimer's Disease

Abstract

Cov kab mob neurodegenerative zoo li Alzheimer's, Parkinson's, thiab Huntington's kab mob cuam tshuam nrog kev sib sau ua ke thiab sib sau ua ke ntawm cov protein muaj kuab lom. Kev hloov pauv tom qab kev txhais lus (PTMs) ntawm cov proteins uas ua rau muaj lub luag haujlwm tseem ceeb hauv etiology ntawm tus kab mob vim tias lawv tuaj yeem ua rau qeeb lossis ua kom cov kab mob nce ntxiv. Alzheimer's kab mob yog txuam nrog kev sib sau ua ke thiab sib sau ua ke ntawm ob qhov loj protein aggregates - intracellular neurofibrillary tangles ua los ntawm microtubule-ssociated protein Tau thiab extracellular Amyloid-plaques. Kev hloov pauv tom qab kev txhais lus yog qhov tseem ceeb rau kev tswj hwm ntawm Tau's kev ua haujlwm tab sis qhov tsis sib xws hauv PTMs tuaj yeem ua rau Tau ua haujlwm tsis zoo thiab sib sau ua ke. Tau methylation yog ib qho tseem ceeb PTMs ntawm Tau hauv nws lub cev lub cev. Txawm li cas los xij, qhov kos npe methylation ntawm Tau lysine hloov thaum nws tau txais ib daim ntawv sib sau ua ke. Tau methylation tuaj yeem sib tw nrog lwm PTMs xws li acetylation thiab ubiquitination. Lub xeev ntawm PTM ntawm cov chaw no txiav txim siab txoj hmoo ntawm Tau protein nyob rau hauv cov nqe lus ntawm nws txoj haujlwm thiab kev ruaj ntseg. Lub ntiaj teb methylation hauv neurons, microglia, thiab astrocytes tau koom nrog ntau lub zog ntawm tes uas cuam tshuam nrog lawv lub luag haujlwm hauv kev tswj hwm ntawm noob caj noob ces ntawm DNA methylation. Ntawm no, peb tau tham txog cov txiaj ntsig ntawm methylation ntawm Tau muaj nuj nqi hauv qhov chaw tshwj xeeb thiab lawv cov lus sib tham nrog lwm cov kev hloov kho lysine. Peb kuj tau piav qhia txog lub luag haujlwm ntawm methylation hauv epigenetic yam thiab neurodegenerative tej yam kev mob cuam tshuam nrog kev tsis sib xws hauv methylation metabolism cuam tshuam rau lub ntiaj teb methylation xeev ntawm cov hlwb.

Ntsiab lus

Tau, Methylation, Methyltransferases, Post-translational modifications, Epigenetics, Aggregation.

Nyem qhov no kom tau txaisDab tsi yog qhov cuam tshuam ntawm Cistanche

Keeb kwm

Alzheimer's tus kab mob yog txuam nrog misfolding ntawm loj ob proteins. Amyloid-peptide aggregates extracellularly thiab yog generated los ntawm cov cleavage ntawm membrane-associated amyloid precursor protein (APP). Tau yog ib qho tseem ceeb ntawm cov protein uas koom nrog hauv kev ruaj khov ntawm microtubules hauv neuronal axons uas tsim intracellular neurofibrillary tangles (NFTs) [1]. Microtubules ua haujlwm raws li cov lem rau lub molecular motors kinesin thiab dynein nqa tawm intracellular thauj thiab tshem tawm cov tsub zuj zuj ntawm cov proteins lom. Tau malfunction ua rau muaj qhov tsis xws luag hauv qhov kev thauj mus los no ua rau cytotoxicity thiab neurodegeneration vim lawv tuaj yeem nthuav tawm thiab ua rau muaj toxicity hauv lwm lub hlwb [2–4]. Neurofibrillary tangles yog cov yam ntxwv ntawm Alzheimer's kab mob thiab muaj feem xyuam rau cov neurodegenerative Tauopathies nyob rau hauv uas Tau yog lub ntsiab tivthaiv [5, 6]. Tau yog cov protein ntau soluble tab sis nws qhov txawv txav tom qab kev hloov pauv hloov pauv cuam tshuam rau nws cov qauv tsis sib xws thiab nws lub peev xwm los koom nrog microtubules [7-9]. Kev ua haujlwm thiab cov qauv ntawm Tau nyob ntawm qhov chaw ntawm lub cellular nrog rau kev hloov pauv tom qab kev txhais lus [10]. Phosphorylation yog suav tias yog ib qho tseem ceeb PTM ntawm Tau raws li nws muaj feem xyuam rau hauv ob qho tib si lub cev thiab lub xeev pathological. Phosphorylation yog yuav tsum tau rau Tau lub koom haum nrog microtubules. Txawm li cas los xij, hyperphosphorylation ntawm Tau ua rau nws qhov kev sib cais ntawm microtubules thiab ua rau kev sib sau ua ke [10-12]. Lub xeev phosphorylated Tau, nyob rau hauv lem, nyob ntawm theem ntawm kinase kev ua si thiab qhov sib npaug ntawm kinases thiab phosphatase hauv neurons [13]. Daim ntawv qhia txog PTMs hauv Tau cov protein tau los ntawm AD cov neeg mob lub hlwb tau nthuav tawm cov chaw phosphorylation, uas tsis muaj nyob rau hauv ib txwm muaj [14]. Qee qhov chaw pathological tseem ceeb suav nrog AT8 (pS202/pT205), AT100 (pT212/pS214), AT180 (pT231/pS235), PHF1 (pS396/pS404), pS356, pY394, pT4129, pS, Feem ntau ntawm cov chaw no nyob hauv cheeb tsam rov qab thiab thaj tsam flanking (N thiab C-terminal) ntawm Tau. Kev hloov kho ntawm qee qhov chaw yuav ua rau muaj kev sib sau ua ke los ntawm kev cuam tshuam cov nqi xa tawm thiab hloov pauv kev sib cuam tshuam intramolecular [15–18]. Ntau tsev neeg ntawm kinases nqa tawm phosphorylation ntawm Tau. Cov no suav nrog proline-directed protein kinases-zoo li GSK-3 , CDK5, thiab MAP kinases (mitogen-activated protein kinases); nonproline-directed protein kinases-zoo li CK (casein kinase), MARKs (microtubule-affinity regulating kinases), PKA (protein kinase A) thiab tyrosine tshwj xeeb kinases-zoo li SFKs (Src tsev neeg kinases) [19]. Cov qib thiab kev ua haujlwm ntawm cov kinases no tau nce siab nyob rau hauv rooj plaub ntawm AD thiab feem ntau ntawm cov no tau pom tias muaj kev sib koom ua ke nrog NFTs. Tau hyperphosphorylation tshwm sim thaum muaj qhov nce hauv phosphorylation piv txwv li muaj qhov tsis sib xws ntawm phosphorylation thiab dephosphorylation. Cov mob no feem ntau tshwm sim vim qhov nce hauv kinase kev ua si nrog rau inhibition ntawm cov protein phosphatase. PP2A (Protein phosphatase 2A) yog qhov loj phosphatase ntawm tes nrog ze li 70 feem pua ​​​​ntawm tag nrho cov cellular phosphatase kev ua [20–22]. PP2A yog tswj los ntawm ob hom-methylation thiab kev ua ntawm endogenous cellular inhibitors hu ua I1 thiab I2. Kev ua PP2A tuaj yeem txo qis txog 50 feem pua ​​​​hauv AD vim yog hypomethylation lossis nce qib ntawm nws cov inhibitors [23].

Qhov tseem ceeb, muaj 11 qhov chaw paub methylation ntawm Tau nyob rau hauv physiological tej yam kev mob thaum lub sij hawm aggregation; qhov loj methylation yog txo. 7 qhov chaw methylation tau pom hauv Tau tam sim no ua khub helical filaments (PHFs) [24, 25]. Cov methylation ntawm cov chaw no muaj feem cuam tshuam nrog qhov tshwm sim ntawm phosphorylation ntawm serine ntawm cov motifs. Muaj cov kev tshawb fawb, uas tau qhia txog kev koom tes ntawm Tau phosphorylation (pT181) nrog nce qib ntawm tag nrho homocysteine ​​thiab txo S-adenosyl methionine: S-adenosyl homocysteine ​​ratio hauv cerebrospinal kua (CSF) [26, 27]. Kev nce qib homocysteine ​​​​yog qhov qhia tau tias muaj peev xwm methylation hauv cov hlwb. Protein phosphatase 2A (PP2A) ua haujlwm ua ib qho enzyme nquag hauv nws lub xeev methylated uas qhia tau hais tias cov nyhuv ntawm aberrant methylation muaj peev xwm ntawm phosphorylation ntawm Tau [28- 30]. Sib nrug los ntawm qhov cuam tshuam ncaj qha ntawm methylation ntawm Tau phosphorylation, methylation tuaj yeem ua lub luag haujlwm tseem ceeb hauv kev hloov pauv ntawm Tau aggregation propensity. Nyob rau hauv-vitro Tau methylation tau pom tias txo cov kev sib sau ua ke ntawm Tau yam tsis muaj kev cuam tshuam nws lub peev xwm kom ruaj khov microtubule sib dhos. Microtubule polymerization yog hampered nkaus xwb nyob rau hauv lub xub ntiag ntawm Tau methylated nyob rau hauv siab stoichiometries. Methylated Tau tsim cov fibrils zoo ib yam li tsis hloov pauv tau tab sis tag nrho cov kev sib sau ua ke thiab qhov tseem ceeb ntawm Tau los pib qhov kev sib sau ua ke tau pom tias tau nce siab [24].

Methylation yog ua los ntawm chav kawm ntawm enzymes hu ua methyltransferases. Class II methyltransferases yog SET domain-muaj enzymes uas feem ntau ua haujlwm raws li histone methyltransferases [31–33]. Txawm li cas los xij, muaj cov methyltransferases ntawm tib chav kawm xws li G9a thiab SUV39, uas txav nruab nrab ntawm cov nucleus thiab cytoplasm los ua rau cytoplasmic proteins [34, 35]. Lysine residues nyob rau hauv ib tug protein yuav raug rau methylation, acetylation, ubiquitination, SUMOylation, thiab glycation (Fig. 1) [9, 36, 37]. Ib qho ntawm cov cwj pwm tseem ceeb ntawm kev hloov pauv tom qab kev hloov pauv ntawm lysine residue yog qhov muaj peev xwm ntawm kev sib tw rau kev hloov kho ntawm ib qho chaw tshwj xeeb. Lub xeev ntawm kev hloov kho tuaj yeem txiav txim siab txoj haujlwm ntawm cov protein. Muaj kev sib raug zoo ntawm methylation nrog lwm cov kev hloov kho lysine feem ntau yog acetylation thiab ubiquitination hauv Tau protein [9, 25, 29]. Kev nyob ntawm ib qho lysine residue nrog methylation, acetylation, lossis ubiquitination tuaj yeem tsav txoj hmoo ntawm Tau protein nyob rau hauv ntau cov lus qhia. Yog li, nws yog ib qho tseem ceeb los kawm txog qhov xwm txheej ntawm kev sib tham sib tham tshwm sim ntawm tag nrho cov PTMs kom nkag siab zoo txog cov txheej txheem ntawm Tau ua haujlwm hauv kev noj qab haus huv thiab kab mob. Tsis tas li, muaj peev xwm sib tham ntawm methylation nrog phosphorylation ntawm PHF6 thiab PHF6 * motifs (VQIINK thiab VQIVYK), qhov twg acetylation zoo li ua lub luag haujlwm tseem ceeb raws li tau hais los ntawm qee qhov kev tshawb fawb [38, 39]. Txawm li cas los xij, kev tshawb nrhiav ntxiv yuav tsum tau nkag siab txog cov txheej txheem hauv qab uas cuam tshuam nrog kev sib tham ntawm cov tshuaj methylation thiab phosphorylation.

Tau methylation hauv Alzheimer's disease

Tau tuaj yeem raug rau mono-methylation lossis di-methylation, uas txiav txim siab lawv txoj haujlwm tswj hwm, tab sis txog tam sim no, tri-methylation tsis tau tshaj tawm hauv Tau [9, 24]. Piv txwv li, qhov luaj li cas ntawm methylation ntawm cov chaw tshwj xeeb yog inversely proportional to the aggregation propensity of Tau. Tau methylation tshwm sim ntawm ob peb lysines thiab ob peb arginine residues los ntawm kev ua ntawm enzymes hu ua lysine methyl transferases los yog arginine methyl transferases. Txawm li cas los xij, tsis paub ntau txog cov methyl transferases koom nrog kev hloov kho ntawm Tau protein. Muaj ib daim ntawv tshaj tawm tsis ntev los no los ntawm Bachmann li al., ntawm lub luag haujlwm ntawm methyl transferase SETD7 ntawm Tau mono-methylation ntawm K130 thiab nws nyob ze lysine residue K132 thiab nws qhov tseem ceeb hauv nuclear Tau localization [40]. Feem ntau ntawm cov chaw methylation nyob hauv thaj tsam microtubule-binding ntawm Tau [9, 24, 25]. Txhawm rau nkag mus rau lub luag haujlwm ntawm methylation ntawm Tau ntawm MTBR, Funk li al., tau ua nyob rau hauv vitro tubulin polymerization assay nyob rau hauv tsis muaj Tau thiab lub xub ntiag ntawm synthetically methylated los yog unmodified Tau. Nws tau pom tias Tau methylation tsis cuam tshuam rau qhov ntawm tubulin polymerization hauv nws lub xeev methylated. Tubulin polymerization tau pom tias muaj kev nyuaj siab nkaus xwb nrog Tau muaj ntau dua stoichiometries ntawm methylation. Tsis tas li ntawd, qhov kev sib sau ua ke ntawm Tau tau pom tias muaj kev cuam tshuam rov qab rau qhov methylation [24].

Nws tau kawm tias qhov chaw ntawm mono-methylated qhov chaw nce nrog kev laus thiab kev loj hlob ntawm AD. Lub pas dej ua ke ntawm tau soluble Tau kuj muaj cov chaw methylated arginine nyob rau hauv lub hlwb ib txwm. Tam sim no kev paub txog qhov cuam tshuam ntawm Tau methylation hauv AD qhia tias methylation yog ib feem ntawm ob qho tib si Tau thiab nws daim ntawv pathological li PHFs. Arginine residues R126, R155, thiab R349 paub tias yog mono-methylated hauv ob qho tib si thiab pathological Tau [41]. Arginine methylation hauv Tau yog xav tias yuav koom nrog hauv daim nyias nyias ntawm Tau thiab nws cov nucleo-cytoplasmic shuttling [42, 43]. Txawm li cas los xij, cov txheej txheem ntawm cov txheej txheem no tsis meej. Kev hloov pauv hauv methylation kos npe tshwm sim hauv AD, uas tuaj yeem hloov pauv lub zog intramolecular hauv Tau molecule uas ua rau muaj kev hloov pauv hauv zos. Cov kev hloov nyob rau hauv lub zos conformations nyob rau hauv lem cuam tshuam lub solubility thiab binding zog. Yog li, cov txheej txheem ntawm PTMs txiav txim siab solubility thiab aggregation propensity ntawm Tau. Ntau qhov chaw phosphorylation thiab methylation hauv Tau muaj nyob ze, uas tuaj yeem hloov qhov tshwm sim ntawm ob qho kev hloov kho. Piv txwv li, Tau phosphorylation ntawm S262 tau pom tshwm sim ntau zaus nrog rau methylation ntawm K267 [25]. Tsis tas li ntawd, methylated Tau tau nthuav dav hauv thaj tsam cuam tshuam ntawm lub hlwb tau los ntawm cov neeg mob AD. Te Tau lesions nyob rau hauv lub hlwb AD tau qhia txog kev tiv thaiv kab mob rau methylated Tau thaum sau npe nrog anti-meK (anti-methylated lysine) antibody [25].

Tus qauv ntawm methylation ntawm ib txwm Tau thiab PHFderived Tau muab cov lus qhia tseem ceeb rau nws txoj haujlwm tswj hwm hauv kev sib sau. Ib txwm Tau hauv tib neeg lub hlwb tuaj yeem yog mono-methylated lossis di-methylated thaum Tau hauv PHFs tsuas yog mono-methylated [37]. Muaj yim lysine residues, uas yog dimethylated tawm ntawm tag nrho ntawm kaum ib qhov chaw methylation hauv Tau. Tsis tas li ntawd, muaj tsawg dua qhov chaw methylation hauv PHF-derived Tau piv rau Tau. Lub xub ntiag ntawm methylated Tau nyob ib puag ncig ntawm qhov chaw phosphorylation, tshwj xeeb tshaj yog nyob rau hauv KXGS motifs yuav muab lub luag haujlwm tiv thaiv phosphorylation. Tsis tas li ntawd, ob qhov chaw methylation ntawm K24 thiab K44 nyob ib sab ntawm qhov chaw caspase thiab calpain cleavage sites thaum lwm tus tsim cov khoom tawg, uas yog aggregates prone [44–46]. Muaj qee qhov kev tshawb fawb txog lub luag haujlwm ncaj qha ntawm methylation ntawm Tau kev ua haujlwm thiab kev sib sau ua ke tab sis cov kev paub tam sim no qhia tias nws yuav muaj lub luag haujlwm tseem ceeb hauv kev txiav txim siab txoj hmoo ntawm Tau.

Cistanche ntsiav tshuajthiabCov txiaj ntsig Cistanche

Methylation ua ib hom kev tswj hwm epigenetic thiab nws lub luag haujlwm hauv Alzheimer's disease

Hauv cov xwm txheej neurodegenerative, methylation koom nrog tsis tsuas yog PTM ntawm Tau, tab sis kuj tseem ceeb heev txog nws lub luag haujlwm hauv kev tswj hwm epigenetic thiab metabolic yam. Alzheimer's kab mob yog txuam nrog ntau yam kev hloov pauv hauv epigenetic pleev ntawm neural hlwb nrog rau cov neurons, microglia, thiab astrocytes [47-50]. Nyob rau hauv microglia, lub enhancer ntawm zest homolog 2 (EZH2) ua hauj lwm nrog rau cov catalytic subunit ntawm polycomb repressive complex 2 mus nqa tawm transcriptional silencing. Cov complex no koom nrog hauv tri-methylation ntawm H3K27 (H3K27me3) [51]. Microglia tau hloov pauv ntau zaus hauv lawv cov tshuaj pleev epigenetic thiab qhia txog kev hloov pauv phenotypic thaum stimulation [52]. Nws tau pom tias microglia pre-exposed nrog LPS lossis TLR4 ligand tau txais cov kev hloov pauv hauv cov tshuaj pleev ib ce hauv lawv cov xeev primed thiab unprimed [51]. Hloov pauv, nyob rau hauv lub xeev kev tiv thaiv kab mob, cov qib methylation ntawm H3K3Me3 tau pom tias yuav txo qis. Hauv cov hlwb neuronal, CpG hypomethylation ntawm tus txhawb nqa ntawm brca1 (mob cancer mis 1) tshwm sim [53]. BRCA1 downregulation ua rau muaj teeb meem nyob rau hauv ob-stranded DNA tawg kho thiab thaum kawg ua rau neuronal tuag (Fig. 2). Te epigenetic regulation ntawm noob qhia tshwm sim los ntawm methylation nyob rau hauv ob txoj kev - hloov ntawm lysine residues nyob rau hauv histone core thiab methylation ntawm CpG dinucleotides [54-57]. Txawm li cas los xij, muaj qhov tshwm sim ntawm non-CpG methylation. Ob qho tib si, methylation ntawm histone lysine thiab DNA methylation ua haujlwm rau lub hom phiaj ntawm gene silencing thiab transcriptional suppression. Cov pawg ntawm CpG hu ua CpG Islands feem ntau muaj nyob rau hauv qhov kev txhawb nqa thiab txhim kho thaj tsam ntawm cov noob. Cov Islands tuaj CpG no muaj methylated lossis hydroxymethylated cytosines li 5-methyl cytosine (5mC) thiab 5-methyl hydroxy cytosine (5hmC) [58–60]. 5mC yog txuam nrog gene repression thaum hloov dua siab tshiab ntawm 5mC rau hauv 5mC sawv cev rau gene activation [61, 62]. Methylation ntawm CpG cuam tshuam qhov kev sib txuas ntawm cov ntsiab lus hloov pauv xws li Ets-1 nrog rau cov tswv tsev 5mC khi cov proteins xws li MeCP2, MBD1, MBD2, thiab MBD4, uas ua haujlwm raws li kev hloov pauv hloov pauv [63]. Sib nrug los ntawm DNA methylation ntawm CpG qhov chaw, kuj tseem muaj ntau ntawm CpH (H hais txog A, T, lossis C) qhov chaw uas yog methylated [64, 65].

Muaj tsib hom DNA methyl transferases koom nrog hauv kev hloov ntawm methyl pawg los ntawm S-adenosyl-L-methionine rau nucleotides hauv DNA – DNMT1, DNMT2, DNMT3a, DNMT3b, thiab DNMT3L [66, 67]. Tawm ntawm cov DNMT1 no feem ntau yog koom nrog hauv kev saib xyuas ntawm methylation kos npe ntawm DNA. Hauv Alzheimer's tus kab mob, muaj pov thawj ntawm kev txo qis 5mC qib thiab DNA methyl transferase 1 (DNMT1) hauv cheeb tsam hippocampal thiab sab hauv lub hlwb [68, 69]. Txawm li cas los xij, hauv lwm txoj kev tshawb fawb, nce qib ntawm DNA methylation thiab DNMTs tau pom nyob rau hauv frontal cortex, temporal cortex, thiab cerebellum [70–72]. DNA methylation yog lub zog muaj zog ntawm kev tswj cov noob ntawm qib epigenetic, xws li cov npe methylation hloov pauv ntawm cov noob caj noob ces nyob ntawm cov kab mob ntawm tes. Methylation theem ntawm CpG Islands nyob rau hauv kev txhim kho thiab txhawb cov cheeb tsam tau kawm nyob rau hauv AD, uas qhia tau hais tias epigenetic dysregulation nyob rau hauv enhancers ntawm noob tseem ceeb heev rau neuronal noj qab haus huv [73, 74]. Kev poob ntawm methylation ntawm CpH ntawm kev txhim kho thiab cov neeg txhawb nqa tau pom nyob rau hauv AD cov xwm txheej uas ua rau muaj kev txhim kho cov hom phiaj qhia. Qhov txo qis ntawm methylation ntawm cov noob hom phiaj no cuam tshuam nrog kev cuam tshuam ntawm apoptotic thiab inflammatory pathways [73–76]. Ib yam li ntawd, txo methylation ntawm bace1 enhancer ua rau overproduction ntawm BACE1 uas nyob rau hauv lem ua rau amyloid- ntau lawm [73, 77]. Upregulation ntawm BACE1 qib kuj tseem cuam tshuam nrog hypomethylation ntawm kev txhim kho cov ntsiab lus hauv Down syndrome cell adhesion molecules zoo li 1 (DSCAML1). Qhov no ua rau muaj kev tswj hwm ntau dhau ntawm bace1 nyob rau theem pib ntawm AD [73]. Ntau qhov kev hloov pauv hauv kev txhim kho methylation dag nyob rau hauv cov noob tswj kev qhia ntawm lub voj voog ntawm tes tswj cov proteins xws li cyclin-dependent kinases (CDKs). Txo cov tshuaj methylation ntawm CDKs txhawb nqa lawv cov qib thiab cuam tshuam kev tswj lub voj voog ntawm tes [78–80]. Qhov no ua rau lub voj voog neuronal rov nkag mus sai sai uas ua rau rho menyuam vim tsis muaj kev tswj hwm txoj cai [79]. Qhov no ua rau kev nce qib ntawm kev tuag neuronal thiab poob synaptic ua rau neurodegeneration. Qhov tshwm sim ntawm DNA hypomethylation ntawm kev txhim kho yog txuas nrog kev tsim ntawm amyloid- aggregates nyob rau theem pib ntawm AD [73].

Muaj cov kev soj ntsuam tsis sib xws txog qib ntawm methylation ua rau nws nyuaj rau kev nkag siab txog lub luag haujlwm ntawm DNA methylation hauv neurodegeneration. Yog li, cov txiaj ntsig ntawm methylation tuaj yeem nyob ntawm tsis yog nyob ntawm qib tab sis ntawm qhov chaw ntawm DNA methylation. Cov qauv tshwj xeeb ntawm DNA methylation thiab cov kab lus gene yog txuam nrog cov xwm txheej ntawm lub cev thiab cov kab mob pathological [81–85]. Kev tshawb fawb ntxaws txog AD tshwj xeeb methylation kos npe ntawm DNA tuaj yeem muab ib qho tseem ceeb biomarker rau kev ntsuam xyuas cov kev pheej hmoo, kev vam meej, thiab kev tshawb pom ntawm AD.

Cistanche extract

Hla tham ntawm Tau methylation nrog lwm tus PTMs

PTMs yog hom kev tswj hwm ntawm ntau cov txheej txheem ntawm tes, uas lawv tus kheej tau tswj hwm. Cov txheej txheem ntawm PTMs ntawm cov protein tsim cov cai uas txiav txim siab nws cov qauv thiab kev ua haujlwm. Qhov tshwm sim ntawm ntau qhov kev hloov kho lossis qhov tshwm sim ntawm ib qhov chaw raug hloov kho los ntawm PTMs sib txawv yog qhov tseem ceeb rau kev ua haujlwm ntawm cov protein thiab sib txawv raws li cov cellular ib puag ncig. Ntau yam lysine residues ntawm Tau yog raug rau ntau tshaj ib hom kev hloov kho. Piv txwv li, K180 tuaj yeem ua acetylated lossis methylated, K254 thiab K290 tuaj yeem ua methylated lossis ubiquitinated, thiab K385 tuaj yeem ua methylated lossis SUMOylated [9, 36]. Lub xeev ntawm PTM ntawm ib qho residue yog tus yam ntxwv ntawm Tau functional state.

Muaj pov thawj rau kev sib tham sib tham ntawm methylation, acetylation, ubiquitination, thiab SUMOylation, nrog rau ib qho PTM tau nyiam raws li qhov xwm txheej. Ubiquitination ntawm K254 yog qhov tseem ceeb hauv lub cev lub cev kom tswj tau Tau homeostasis [25, 86]. Hauv AD, theem ntawm Tau methylation ntawm K254 tshaj nws qib ubiquitination hauv PHFs, cuam tshuam qhov kev tshem tawm ntawm Tau aggregates los ntawm ubiquitin proteasomal system (UPS) [25]. Txawm li cas los xij, lwm cov lysine residue K290 tau pom tias muaj nyob rau hauv aggregated Tau thaum methylated hauv ib txwm muaj [41]. Ubiquitination kuj tseem muaj peev xwm sib tham nrog phosphorylation vim nws pom tias Tau ubiquitination hauv PHFs cuam tshuam nrog phosphorylation raws li nws ua ntej ubiquitination thiab koom ua ke rau hauv PHFs [87-90]. Ib yam li ntawd, acetylation li PTM paub txog nws lub luag haujlwm hauv Tauopathies. Tau protein ntau li PHF yog acetylated heev nyob rau hauv lub xeev pathological piv rau physiological mob. Lysine residues K163, K174, thiab K180 tej zaum yuav raug rau acetylation los yog methylation nyob rau hauv pathological thiab physiological xeev feem [37, 91]. Methylation ua haujlwm tseem ceeb hauv kev ruaj ntseg ntawm Tau protein. Yuav muaj kev sib tham sib tham ntawm Tau methylation thiab phosphorylation, qhov twg ob qhov chaw nyob ib sab. Piv txwv li, peb ntawm lysines hauv KXGS motifs (K259, K290, thiab K353) yog methylated nyob rau hauv physiological mob [24, 37]. Kev hloov kho Lysine ntawm KXGS motifs zoo heev txo cov phosphorylation muaj peev xwm ntawm cov serine uas nyob ib sab cuam tshuam rau kev tiv thaiv lub luag haujlwm ntawm methylation. Txawm li cas los xij, lysine acetylation ntawm KXGS motif pom muaj nyob rau hauv PHFs thiab paub tias yuav ua rau kom cov hyperphosphorylation ntawm Tau [92]. Feem ntau ntawm cov chaw rau methylation muaj nyob rau ntawm thaj chaw microtubule-binding (MTBR), uas peb qhov chaw sib tshooj nrog ubiquitination [24, 25]. Acetylation ntawm K163, K174, thiab / lossis K180 tau tshaj tawm tias tshwm sim hauv vivo, thaum acetylation nyob nce nrog kev nce qib ntawm AD. Cov chaw hauv (K274 thiab K280) lossis nyob ib sab (K259 thiab K353) rau PHF6 * hauv MTBR kuj pom tias yog acetylated [9, 37]. SUMOylation ntawm Tau tshwm sim feem ntau nyob rau hauv ob qhov chaw - K340 thiab K385, ob qho tib si ntawm cov uas pw hauv thaj tsam rov ua dua ntawm Tau [93]. SUMOylation ntawm K340 tau paub tias muaj kev cuam tshuam rau cov kab mob vim nws cuam tshuam nrog Tau phosphorylation ntawm ADassociated phospho-epitopes xws li T231 thiab S262 [94]. Txawm hais tias, SUMOylation ntawm K340 paub tias muaj lub luag haujlwm pathological; K385 ua haujlwm raws li qhov chaw rau methylation thiab ubiquitination ib yam nkaus, qhia nws txoj haujlwm txiav txim siab hauv neurodegeneration. Qhov ua tau ntawm kev hloov kho ntawm ib qhov chaw los ntawm cov ntawv PTM sib txawv (methylation, acetylation, thiab lwm yam) tuaj yeem tsav mus rau ntau txoj hmoo ntawm Tau protein (Fig. 3). Te tam sim no cov pov thawj ntawm ntau yam PTM hla kev sib tham qhia tias kev sib tw rau lysine residues tuaj yeem tswj hwm lub xeev ua haujlwm nrog rau kev hloov pauv ntawm Tau protein.

Kev tswj hwm ntawm Tau methylation thiab nws cov txiaj ntsig metabolic hauv kev noj qab haus huv neuronal

Cov xwm txheej ntawm tag nrho cov methylation / demethylation hauv hlwb nyob ntawm lub pas dej ntawm universal methyl pab pawg neeg pub dawb xws li S-adenosyl methionine (SAM) muab tau los ntawm methionine. SAM, thaum pub dawb methyl pawg tau hloov mus rau S-adenosyl homocysteine ​​(SAH), uas nyob rau hauv lem tau hydrolyzed rau homocysteine ​​nyob rau hauv ib tug reversible cov tshuaj tiv thaiv (Daim duab 4) [95–97]. Homocysteine ​​​​ tuaj yeem hloov rov qab mus rau methionine los ntawm enzyme methionine synthase nyiam qhov zoo tshaj plaws methylation muaj peev xwm nyob rau hauv ib lub xovtooj ntawm tes lossis hloov mus rau hauv cysteine ​​hauv cov tshuaj tiv thaiv trans-sulfuration siv folate [98, 99]. Yog li, qhov piv ntawm SAM thiab SAH yog qhov tseem ceeb ntawm kev txiav txim siab ntawm methylation muaj peev xwm qhov twg qib siab dua tom qab qhia txog kev cuam tshuam ntawm cellular methylation [100]. Cov metabolism ntawm methyl pawg hauv hlwb yog suav tias yog ib qho tseem ceeb ntawm kev noj qab haus huv neuronal vim muaj kev koom tes ntawm cov tshuaj methylation hauv ntau cov txheej txheem tswj hwm xws li kev tsim cov noob ntawm DNA methylation, kev tswj hwm epigenetic los ntawm kev hloov kho histone, neurotransmitter metabolism, lub luag haujlwm hauv phospholipid synthesis thiab myelin tsim. [101–108].

Qhov tsis sib xws hauv Tau phosphorylation tshwm sim los ntawm kev ua haujlwm dhau ntawm kinase lossis txo qis phosphatase kev ua haujlwm. Hauv AD, Tau hyperphosphorylation tuaj yeem tshwm sim yog tias PP2A kev ua haujlwm raug txwv tsis pub muaj kev hloov pauv ntawm kinase kev ua haujlwm [109]. Qhov qis dua ntawm SAM: SAH yog qhov tseem ceeb hauv Tauopathies, vim tias muaj kev sib raug zoo ntawm kev cuam tshuam ntawm cellular methylation thiab hyperphosphorylation ntawm Tau [110]. Hauv qhov no, PP2A yog ib qho tseem ceeb ntawm cov protein phosphatase paub los tswj lub xeev phosphorylation ntawm Tau. PP2A muaj peb lub subunits hauv nws daim ntawv nquag-A, B, thiab C [111–113]. Kev tsim cov enzymes nquag yog tswj hwm los ntawm kev thim rov qab methylation ntawm C-terminal ntawm subunit C, uas tswj kev tsim cov enzyme heterotrimer. Tsis tas li ntawd, methylation tshwm sim ntawm AC dimer, uas tau pom los txhawb nws txoj kev sib raug zoo rau subunit B [113]. Yog li, methylation plays lub luag haujlwm tseem ceeb hauv kev ua kom PP2A. SAH tsim los ntawm SAM-mediated methylation ua rau homocysteine ​​​​tau hloov mus rau methionine lossis tuaj yeem hloov mus rau SAH los ntawm kev koom nrog adenosine [114]. Qee yam kev pheej hmoo xws li folate (yuav tsum tau ua rau cov tshuaj tiv thaiv kab mob sib kis) lossis cobalamin (yuav tsum tau hloov pauv homocysteine ​​rau hauv methionine) tsis txaus, noj zaub mov tsis zoo, yam caj ces, thiab lwm yam. txhawb nqa SAH ntau ntxiv [97, 115–117]. Kev sib sau ntawm SAH txhawb nqa tag nrho hypomethylation nyiam qhov depletion ntawm methyl pub SAM pas dej ua ke nrog rau kev sib tw inhibitor ntawm methyl transferase enzymes. Kev nce homocysteine ​​feem ntau yog suav tias yog biomarker hauv cov kab mob vascular [118-120]. Metabolic defects ua rau homocysteine ​​tsub zuj zuj yog paub los cuam tshuam kev txawj ntse ntawm ntau yam mechanisms [121, 122]. Homocysteine ​​​​yog lub luag haujlwm cuam tshuam rau kev noj qab haus huv neuronal ntawm oxidative kev nyuaj siab, amyloid- deposition, thiab txhawb Tau phosphorylation [123–130]. Homocysteine ​​​​ntau ntau tuaj yeem suav tias yog ob qho kev pheej hmoo thiab tus cim kab mob. Yog li, kev tsom mus rau qib siab homocysteine ​​​​tuaj yeem pab tshawb xyuas qhov kev loj hlob ntawm AD.

Cov ntsiab lus thiab cov lus qhia yav tom ntej

Qhov tshwm sim thiab kev loj hlob ntawm Alzheimer's tus kab mob nyob ntawm ntau yam ntawm cov xwm txheej, ntawm qhov kev hloov pauv tom qab kev hloov pauv ntawm cov protein tseem ceeb ua lub luag haujlwm tseem ceeb. Tau raug rau ntau tus PTMs ntawm ntau qhov chaw thiab hais txog PTMs ntawm Tau, phosphorylation tau kawm zoo thiab pom tias muaj lub luag haujlwm tseem ceeb hauv kev kis kab mob. Txawm li cas los xij, lub luag haujlwm ntawm methylation yuav tsum tau tshawb nrhiav thiab nkag siab kom meej. Ntawm ib sab, Tau methylation ua haujlwm tiv thaiv kev sib sau ua ke thaum nyob rau lwm qhov, nws yuav muaj txiaj ntsig zoo. Nyob ntawm qhov chaw ntawm methylation thiab nws muaj peev xwm sib tham thiab sib tw rau qhov chaw muaj, cov nyhuv tuaj yeem sib txawv. Lysine residues uas tuaj yeem raug rau ob qho tib si acetylation thiab methylation yog qhov tseem ceeb txog Tau kev ua haujlwm thiab kev ruaj ntseg vim tias acetylation paub tias muaj feem cuam tshuam nrog Tau. Tau PHFs muab los ntawm AD hlwb yog hnyav acetylated ntawm ntau qhov chaw. Kev tiv thaiv kev ua haujlwm ntawm methylation tiv thaiv Tau aggregation tuaj yeem raug ntaus nqi rau qhov nyiam methylation ntawm cov chaw zoo li no. Txawm li cas los xij, lysine residues zoo li K254 uas tuaj yeem raug rau methylation thiab ubiquitination, nthuav tawm qhov sib txawv. Hauv cov xwm txheej zoo li no, methylation tuaj yeem cuam tshuam Tau degradation thiab hloov pauv hauv hlwb los ntawm kev cuam tshuam cov proteasomal degradation ntawm Tau.

Cistanche ntxiv

Kev tswj hwm Epigenetic yog ib qho tseem ceeb ntawm Alzheimer's kab mob raws li kev qhia theem ntawm ntau cov proteins tseem ceeb xws li APP, BACE1, Presenilins, thiab ApoE paub tias nyob rau hauv kev tswj hwm epigenetic. Ntawm no, methylation lub luag hauj lwm raws li ib tug gene repressor ntawm DNA methylation thiab nyob rau hauv chromatin remodeling los ntawm histone lysine hloov kho yog qhov tseem ceeb. Tag nrho cov methylation muaj peev xwm ntawm cov hlwb yog xav tau los tswj cov qib transcriptional ntawm cov noob. Cov xwm txheej uas txhawb nqa hypomethylation tuaj yeem ua rau txhim kho qib ntawm cov ntawv sau cov noob thiab yog li, nce qib protein. Cov proteins uas ncaj qha (APP, Tau, thiab Presenilins) los yog tsis ncaj (BACE1 thiab ntau yam kinases) koom nrog AD kev loj hlob yog upregulated uas ua rau hloov qhov sib npaug ntawm cov kab mob. Tsis tas li ntawd, cov enzymes koom nrog hauv kev tiv thaiv kev ua haujlwm xws li PP2A yog tswj hwm los ntawm methylation. Raws li kev txo qis methylation hauv hlwb, PP2A kev tawm tsam ua rau muaj kev nce ntxiv thiab txawv txav ntawm phosphorylation nrog rau hyperphosphorylation ntawm Tau.

Methylation yog koom ncaj qha rau hauv Tau kev cai raws li cov txheej txheem epigenetic thiab lub xeev hypomethylated hauv cov hlwb yog ib qho ntawm cov laj thawj. Muaj qhov sib npaug sib npaug ntawm qib ntawm universal methyl pab pawg neeg pub dawb SAM thiab nws tus khub SAH uas txiav txim siab tag nrho cov peev txheej methylation. Methyl pab pawg metabolism tsis txaus yuav tshwm sim los ntawm cov khoom siv sab hauv thiab sab nrauv, ua rau qis SAM: SAH piv thiab yog li txo cov peev xwm methylation. Hauv cov xwm txheej zoo li no, qib ntawm plasma homocysteine ​​​​tau nce siab heev uas tau siv los ua tus cim rau kev mob plawv rau lub sijhawm ntev. Txawm li cas los xij, nws qib kuj pom tau tias nce siab hauv cov mob neurodegenerative qhia txog lub luag haujlwm tseem ceeb ntawm methylation.

Methylation tuaj yeem ua tus neeg tawm tsam lossis ua kom muaj cov noob qhia nyob ntawm qhov chaw ntawm kev hloov kho histone lysine [131]. Kev tswj hwm ntawm tshwj xeeb DNMT inhibitors tuaj yeem pab txo cov kab mob pathological uas tshwm sim los ntawm hypermethylation. Hypoxic tej yam kev mob nyob rau hauv cortical thiab hippocampal neurons ua rau muaj zog H3K9Me2 thiab txo H3 acetylation ntawm tus txhawb nqa neprilysin ua rau nws downregulation. Txo cov qib neprilysin txhawb nqa amyloid-plaque tsub zuj zuj vim nws ua haujlwm raws li A degrading enzyme [132]. Diazepinquinazolin-amine derivative-BIX-01294 yog DNMT inhibitor uas tshwj xeeb ua rau methyl transferase G9a [133]. BIX-01294 kev kho mob tau raug tshaj tawm los ua kom rov qab ua cov yas yas hauv cov qauv amyloid-rat [134]. Txawm li cas los xij, feem ntau ntawm cov inhibitors lossis modulators ntawm methylation xws li decitabine (DAC) thiab azacitidine (AZA), tsis yog tshwj xeeb thiab qhia txog cov teebmeem genome thoob ntiaj teb [135]. Yog li, ntiav cov inhibitors lossis modulators uas yog cov neeg ua haujlwm tshwj xeeb uas tuaj yeem ua haujlwm los tswj cov peev txheej methylation yog qhov tsim nyog los tsim cov tswv yim kho mob.

Kev noj zaub mov zoo thiab kev cuam tshuam kev kho mob tuaj yeem pab kho cov qib homocysteine ​​li qub thiab yog li muaj peev xwm methylation. Txij li thaum methylation tau koom nrog ob qho tib si ncaj qha raws li Tau hloov pauv thiab tsis ncaj qha raws li tus qauv epigenetic ntawm AD; nws tuaj yeem ua pov thawj tias yog lub hom phiaj kho mob tseem ceeb rau kev tiv thaiv kab mob. Alzheimer's kab mob yog txuam nrog qis SAM raws li pom nyob rau hauv lub hlwb AD [136, 137]. Hauv AD, cov kev hloov pauv hauv ib-carbon metabolism uas cuam tshuam nrog methylation yog pom tseeb, cuam tshuam lub ntiaj teb methylation muaj peev xwm. Txo methylation muaj peev xwm nyob rau hauv lem ua rau tag nrho hypomethylation. Lub xeev hypomethylated nyob rau hauv neurons yog txuam nrog Tau aggregation, nce Presenilin qhia, thiab amyloid- tsub zuj zuj [138, 139]. Yog li, cov tswv yim kho mob txhawm rau txhawm rau txhawm rau txo qis methylation muaj peev xwm hauv cov neurons tuaj yeem ua pov thawj tias muaj txiaj ntsig zoo hauv kev kho mob AD (Fig. 5). Kev tswj hwm ntawm SAM hauv 3xTg-AD nas tau pom tias muaj txiaj ntsig zoo tiv thaiv amyloid- thiab Tau pathology thiab ua kom cov xwm txheej cuam tshuam nrog kev tshaj tawm xws li genetic predisposition thiab oxidative stress [140, 141].

Cov khoom sib xyaw ntuj tuaj yeem hloov kho lub xeev ntawm DNA methylation tuaj yeem muab txoj hauv kev siv los txo cov kab mob pathological hauv AD. Piv txwv li, Epigallocatechin-3-gallate (EGCG) sib tw inhibits DNMT1 thiab ua rau rov qhia cov noob silenced ntawm DNMT1-mediated methylation [142–144]. Muaj lwm cov molecules me me ntawm lub hauv paus chiv keeb xws li-naringin, apigenin, luteolin, curcumin, genistein, thiab lwm yam, paub tias muaj kev cuam tshuam rau DNA methylation [144-146].

Cov ntaub ntawv

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Abhishek Ankur Balmik1,2 thiab Subashchandrabose Chinnathambi1,2.

1. Neurobiology Group, Division of Biochemical Sciences, CSIR-National Chemical Laboratory (CSIR-NCL), Dr. Homi Bhabha Road, 411008, Pune, India.

2. Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India.