Gauging Lub luag hauj lwm thiab cuam tshuam ntawm kev sib cuam tshuam ntawm cov tshuaj thiab rov ua dua nyob rau hauv Neurodegenerative Disorders Part 3

4.1.1. Genes cuam tshuam nrog lipid metabolism

ABCA7 (ATP binding cassette transporter A7) noob nyob rau ntawm chromosome 19p13.3 yog heev nthuav tawm nyob rau hauv hippocampus CA1 neuron thiabmicroglial hlwb thiab encodes rau ABCA7 rau lipoprotein thauj nyob rau hauv lub cell.

Microglia yog cov paj hlwb tseem ceeb uas muaj lub luag haujlwm los tswj kev ua haujlwm ntawm lub paj hlwb thiab cuam tshuam rau tib neeg kev paub thiab kev nco. Kev loj hlob ntawm lub cev ntawm kev tshawb fawb qhia tau hais tias microglia muaj txiaj ntsig zoo rau tib neeg kev noj qab haus huv thiab kev noj qab haus huv.

Ua ntej, microglia tuaj yeem txhim kho kev nco. Lub cim xeeb tau muab faib ua lub cim xeeb luv luv thiab lub sijhawm ntev, thiab microglia feem ntau koom nrog cov txheej txheem kev paub txog kev nco mus ntev. Thaum tib neeg ua lub cim xeeb ntev, microglia tso cov neurotransmitters rau cov neurons los txhawb kev sib cuam tshuam ntawm cov neurons, yog li ua kom cov txheej txheem nco. Yog li ntawd, rau cov neeg uas xav txhim kho lawv lub cim xeeb, nws yog ib qho tseem ceeb heev uas yuav tsum muaj kev noj qab haus huv ntawm microglia hauv lub hlwb.

Tsis tas li ntawd, microglia tuaj yeem txo qis kev laus ntawm kev paub txog kev puas tsuaj. Raws li peb muaj hnub nyoog, tib neeg lub peev xwm kev txawj ntse kuj maj mam poob, uas feem ntau cuam tshuam nrog kev tuag, atrophy, thiab inactivation ntawm hlwb hlwb. Txawm li cas los xij, kev tshawb fawb qhia tau hais tias microglia tuaj yeem txhawb kev tsim kho dua tshiab thiab tiv thaiv cov neurons thiab txo qhov tshwm sim ntawm kev txawj ntse. Qhov no kuj qhia txog qhov tseem ceeb ntawm kev tswj hwm lub cev ua haujlwm ntawm microglia hauv kev tiv thaiv kab mob xws li Alzheimer's kab mob.

Feem ntau, microglia yog ze ze rau tib neeg kev paub thiab kev nco. Lawv txoj kev noj qab haus huv tsis tsuas yog muaj txiaj ntsig zoo rau tib neeg lub neej zoo, kev txhim kho kev ua haujlwm, thiab lwm yam tab sis kuj tuaj yeem txo cov kev xav txog kev laus thiab kev noj qab haus huv ntawm cov neeg laus. lub neej zoo. Yog li ntawd, peb yuav tsum xyuam xim rau kev noj qab haus huv ntawm microglia thiab txais yuav txoj kev ua neej kom tsim nyog, kev noj haus, thiab kev tawm dag zog los txhawb lawv txoj haujlwm. Nws tuaj yeem pom tias peb yuav tsum txhim kho kev nco, thiab Cistanche deserticola tuaj yeem txhim kho kev nco, vim Cistanche deserticola tseem tuaj yeem tswj hwm qhov sib npaug ntawm cov neurotransmitters, xws li nce qib ntawm acetylcholine thiab kev loj hlob. Cov khoom no tseem ceeb heev rau kev nco thiab kev kawm. Tsis tas li ntawd, Cistanche deserticola kuj tseem tuaj yeem txhim kho cov ntshav khiav thiab txhawb nqa cov pa oxygen, uas tuaj yeem ua kom lub hlwb tau txais cov as-ham txaus thiab lub zog, yog li txhim kho lub hlwb tseem ceeb thiab kev ua siab ntev.

Nyem paub ntxiv los txhim kho kev nco

Hauv GWAS G allele rs3764650 SNP tau pom tias yog qhov muaj feem cuam tshuam rau AD vim tias nws cuam tshuam nrog hippocampal thiab cortical atrophy thiab kev paub tsis meej ntawm cov neeg mob (Almeida li al., 2018).

4.1.2. Gene cuam tshuam nrog kev tiv thaiv kab mob thiab kab mob

Neuroinflammation yog ib qho ntawm cov cim tseem ceeb ntawm AD uas yog cov lus teb ntawm lub cev tiv thaiv kab mob.CR1 nyob ntawm chromosome 1q32 uas tau nthuav tawm dav hauv cov ntshav. CR1 codes rau kev tswj hwm cov protein.

Ib txoj kev tshawb nrhiav pom rs6656401, SNP variant uas muaj feem xyuam nrog LOAD (Lambert li al., 2009).EPHA1 nyob rau ntawm chromosome 7q34 thiab yog ib tug tswv cuab ntawm tsev neeg tyrosinekinase. Cov noob no muaj feem cuam tshuam rau hauv kev tiv thaiv kab mob, kab mob chronicinflammation, synaptic plasticity, thiab cellular membrane txheej txheem. TheSNP, rs11767557 tau cuam tshuam nrog kev pheej hmoo ntawm LOAD (Hollingworth li al., 2011).

TREM2 (Triggering receptor nthuav tawm ntawm myeloid cell 2) noob nyob ntawm chromosome 6q21.1, qhia tau zoo heev ntawm lub xov tooj ntawm tes ntawm microglia thiab thoob plaws hauv nruab nrab paj hlwb, thiab encodes forsingle-pass type 1 membrane (Giri li al., 2016).

Replogle et al. tshaj tawm variant G rs6910730 kom cuam tshuam nrog kev paub tsis meej. Ib qho tsis tshua muaj TREM2 qhov txawv txav T rs75932628 tau cuam tshuam nrog ADpathology (Replogle li al., 2015).

4.1.3. Genes cuam tshuam nrog endocytosis thiab synaptic muaj nuj nqi

CD2AP yog nyob rau ntawm chromosome 6p12, qhia nyob rau hauv lub hlwb thiab cov neeg mob AD, thiab encodes rau CD2-sociated protein uas yog scaffoldingmolecule thiab tswj cov actin cytoskeleton. Nws ua haujlwm koom nrog inreceptor-mediated endocytosis, apoptosis, cell adhesion, thiab intracellulartrafficking. SNP rs9296559 thiab rs9349407 hauv CD2AP yog xav tias yuav yog atrisk ntawm LOAD.

SNP rs9349407 yog txuam nrog cov quav hniav (Shulman li al., 2013). Cov noob CD2AP tau koom nrog LOAD txaus ntshai thiab ua lub luag haujlwm tseem ceeb hauv receptor-mediated endocytosis, uas ntseeg tau tias yuav cuam tshuam thaum lub sijhawm pib ntawm AD (Dunstan li al., 2016).PICLAM (Phosphatidylinositol binding Clathrin assembly protein) islocated on chromosome. 11q14, qhia nyob rau hauv tag nrho cov ntaub so ntswg thiab prominentlyin neurons.

PICLAM tau koom nrog hauv clathrin-mediated endocytosis thiab kuj zoo nkaus li koom nrog kev lag luam ntawm VAMP (Harold et al., 2009). SNP rs3851179 yog txuam nrog cov thickening ntawm lub endorhinal cortexand hippocampal degeneration thiab rs3851179 & APOE ε4 yog txuam nrog lub hlwb atrophy thiab kev txawj ntse poob (Biffi li al., 2010).

4.2. Tus kab mob Parkinson

PD yog qhov thib ob tshaj plaws uas tsis tuaj yeem thim rov qab, nce zuj zus, nyuaj NDafter Alzheimer's, uas cuam tshuam rau yuav luag 2-3% ntawm tag nrho cov neeg muaj hnub nyoog 65 xyoo. Cov txiaj ntsig ntawm neuropathological suav nrog dopaminergic neuronal poob hauv substantia nigra thiab aggregates ntawm -synuclein (Poewe li al., 2017). Los ntawm 1990 mus rau 2016 cov xwm txheej ntawm Parkinson's muaj yuav luag tau nce los ntawm 2.4 npaug (Collaborators thiab GBDPsD, 2018).

PDwa thawj zaug suav tias yog ib qho kev tsis sib xws ntawm caj ces thiab tsuas yog ntawm 'sporadic' keeb kwm, tab sis nyob rau hauv ob peb lub xyoo dhau los, nws tau pom tias muaj kev cuam tshuam nrog keeb kwm ntawm caj ces. Nrog rau cov xwm txheej ib puag ncig, cov xwm txheej keeb kwm muaj feem sib npaug rau kev pheej hmoo ntawm PD. Ntau yam geneticloci thiab cov noob uas cuam tshuam nrog PD yog raws li hauv qab no: PARK1 & PARK4 locus ob leeg yog mapped ntawm chromosome 4q21 thiab thiab txuam nrog SNCA, ib tug gene uas encodes rau -synuclein.

Peb qhov kev hloov pauv tsis tshua muaj tshwm sim: A53T, A30P, thiab E46K tshwm sim hauv SNCA, los ntawm qhov uas A53T tau pom ntau zaus. Duplication thiab triplication ntawm PARK4 raug suav tias yog tshuaj lom. Duplication ntawm cov noob zoo ib yam li idiopathic PDwhile triplicate yog lub luag haujlwm rau kev pib ntxov thiab kev mob sai sai (Lesage and Brice, 2009).

Kev hloov pauv (duplication /-triplication) yog lub luag haujlwm rau kev paub txog kev poob qis, kev ua haujlwm tsis raug cai, thiab kev poob ntawm lub paj hlwb hauv nigral thiab hippocampalregions (Farrer, 2006).PARK2 loci yog npaj rau ntawm chromosome 6q25.2 thiab cuam tshuam nrog cov noob caj ces, mut. ua rau ib qho autosomal recessive daim ntawv ntawm PD.Parkin yog ib qho ubiquitin e3 ligase uas ua haujlwm nrog PINK1 hauv kev tswj cov mitophagy.

Ib txoj kev tshawb fawb tau tshaj tawm tias qhov sib xyaw heterozygotic hloov pauv hauv PARK2 nrog ib qho kev hloov pauv ntawm G403C thiab tshem tawm kev hloov pauv ntawmexon 6 tuaj yeem pab txhawb rau kev txhim kho EOPD (Fang li al., 2019). Cov loci yog txuam nrog Lewy lub cev thiab tau pathology thiab tseem nrog neuronal poob. hauv thaj av nigral.

PARK5: Lub UCHL1 (Ubiquitin carboxyl-terminal esterase L1) geneon loci PARK5 yog nyob ntawm chromosome 4p14, thiab encodes rau ubiquitinthiolesterase. UCHL1 protein yog amply tam sim no nyob rau hauv neurons thoob plaws hauv lub hlwb. Cov protein no yog txuam nrog ubiquitin-proteasome system, uas pab tshem tawm cov proteins uas txawv txav thiab tsis zoo.

Missensemutation hauv cov noob no tshwm sim los ntawm kev hloov cov amino acid leucine nrog methionine ntawm 93 txoj hauj lwm (I93M), uas ua rau muaj kev cuam tshuam hauv kev ua haujlwm ntawm ubiquitin-proteasome system. Qhov kev hloov pauv no cuam tshuam nrog autosomal dominant PD (Selvaraj thiab Piramanayagam, 2019).PARK6: PARK6 locus nyob ntawm chromosome 1p 36 txuam nrog PINK1 (PTEN-induced kinase 1) noob, ib qho mitochondrial serine nrog kinaseonine thiab protein. recessive ntxov ntxov ntawm PD.

PINK1 txoj haujlwm yog txhawm rau txheeb xyuas qhov puas mitochondria los tiv thaiv lawv cov tsub zuj zuj hauv lub cell. PINK1 p.I3689 kev hloov pauv tau pom muaj kev koom tes hauv PD uas cuam tshuam rau kev ua haujlwm kinase thiab PARKINactivation (Ando li al., 2017).PARK7: PARK7 loci txuam nrog DJ-1gene nyob ntawm chromosome 1p36.23, kuj yog lub luag haujlwm rau autosomal recessive PD.

Nws paub tias yuav koom nrog kev tiv thaiv lub hlwb los ntawm oxidative stress.Takahashi-niki K li al. pom 4 mutants txuam nrog DJ-1 ntawm uas ob yog homozygous mutations (L166P, M26I0) thiab ob heterozygous mutations (R98Q, D1498) (Takahashi-Niki li al., 2004). Tom qab kev hloov pauv, qhov kev ua haujlwm ib txwm zoo li nws cov tshuaj tiv thaiv antioxidant thiab neuroprotective los ntawm cov protein ploj.

PARK8: PARK8 locus raug txheeb xyuas ntawm chromosome 12q12, txuam nrog LRRK2 (leucine-nplua nuj rov kinase 2). Nws pab hauv kev thauj mus los hauv vesicular, kev sib cuam tshuam ntawm cov protein-protein, thiab tseem nyob hauv autophagy (Selvaraj thiab Piramanayagam, 2019). Ntau qhov kev hloov pauv tau koom nrog hauv LRRK2 uas tuaj yeem tuav lub luag haujlwm rau phosphorylation ntawm -synuclein thiab tau, ib qho tseem ceeb cuam tshuam nrog kev sib sau thiab sib sau ntawm cov protein ntau hauv ND (Zimprich li al., 2004).PARK9: Nyob ntawm chromosome 1p313 thiab yog txuam nrog (ATP ATPase 13A2) gene.

Ntau qhov kev hloov pauv tsis zoo tau paub tias ua rau PD pathogenicity tab sis qhov tseeb mechanism tseem tsis paub (Klein thiab Westenberger, 2012). Kev hloov pauv hauv ATP13A2 tsis yog koom nrog PD nkaus xwb tab sis kuj muaj lwm yam NDs xws li Kufor-Rabef syndrome thiab neuronal ceroid lipofuscinoses. Ib yam li ntawd, PARK10 txheeb xyuas ntawm chromosome 1p32 tseem yuav cuam tshuam nrog cov noob. Ntxiv rau tag nrho cov kab mob PD no, ob peb PARK loci raug txheeb xyuas los ntawm GWAS rau kev ua rau muaj kab mob hauv cov neeg mob PD.

Hauv kev tshuaj ntsuam meta tsis ntev los no, ntau dua 800 GWAS tau pom ntau qhov chaw cuam tshuam nrog PD xws li CCD62 / H1P1R, ACMSD / THEMI63, DGKQ / GAK, HLA, MCCC1 / LAMP3, ITGA8, STK39, thiab SYT11 / RAB25 (Zhang et al. , 2018a).Lwm yam ND uas muaj ntau yam kev hloov pauv noob hauv lawv cov kab mob yog:

4.3. Ntau yam sclerosis

MS yog ib qho mob ntev, mob, mob autoimmune cuam tshuam rau CNS. Th1 thiab Th17 yog cov kab mob loj tshaj plaws vim lawv tsim cov cytokines thiab chemokines xws li IL-6, IL-9, IL-12, IL-17,IL{{7} }, IL-22, IL-23, IL-26, TNF- , TNF- , and INF- (Jadidi-Niaragh and Mirshafiey, 2011).

Lub IL-6 kev ua haujlwm noob nyob rau ntawm chromosome7p21; Nws yog lub luag haujlwm rau kev ua kom microglia thiab astrocytes, induction ntawm cerebrovascular adhesion molecules, thiab kev thauj mus los ntawm B & Tlymphocytes thoob plaws BBB rau hauv CNS. Ib qho SNP hauv rs1800975 tau pom tias yog qhov pheej hmoo rau MS. Lwm qhov tseem ceeb proinflammatory factorIL-7gene yog pom nyob rau ntawm chromosome 5p13.2, uas encodes rau CD127 protein.

Nws plays lub luag haujlwm tseem ceeb hauv kev hloov pauv ntawm Tlymphocytes. Ib qho kev hloov pauv hauv cov noob SNP rs6897932 hauv exon6 kuj tau pom tias cuam tshuam rau MS. Ib yam li ntawd, IL7RA rs3194051, rs6897932, rs987107, thiab rs11567686 variants tuaj yeem koom nrog hauv kev txhawb nqa caj ces rau MS (Benesova li al., 2018). Tsis tas li ntawd, HLA (Humanleukocyte antigen) DRB1 * 1501 yog ib qho ntawm cov noob loj uas xav tias yuav koom nrog hauv MS (Alcina li al., 2012).

4.4. Amyotrophic lateral sclerosis

ALS yog tus neeg tuag, nce qib ND. Muaj ntau ntau cov noob uas muaj feem cuam tshuam nrog ALS: SOD1gene nyob ntawm chromosome 21q22.1, thiab nws tau sau tseg tias muaj ntau dua 150 qhov kev hloov pauv uas pom tau nthuav dav thoob plaws cov protein ntau.

Xws li aberrant protein aggregates thaum sau, yuav ua rau tuag ntawm lub cev muaj zog neurons ua rau kev loj hlob ntawm ALS phenotype. Tawm ntawm tag nrho cov noob, ib qho geneticmutation hauv SOD1 ib leeg suav txog li 20% ntawm tsev neeg ALS.

Cov noob tseem ceeb no cuam tshuam nrog ALS yog TARDBP nyob rau ntawm chromosome 1 thiab cov lej rau TDP-43 cov protein uas ua lub luag haujlwm tseem ceeb hauv kev tswj hwm RNA splicing thiab thauj. Hauv dysregulated/pathological neurons, TDP-43 tau pom tias muaj nyob rau hauv cytoplasm-forming aggregates (Jeon li al., 2019).

Hauv ib txoj kev tshawb fawb, ib qho kev hloov pauv ntawm txoj hauj lwm 1028 (A1028G) hauv TDP-43 tau pom tias muaj kev cuam tshuam tsis zoo rau ALS (Yokoseki li al., 2008). Lwm cov noob hloov pauv uas cuam tshuam nrog kev loj hlob ntawm ALS yog ANG, FUS, VCP, OPTN, C9Oorf72, UBQLN2, SQSTM1, MATR3, thiab TBK1 (Taylor li al., 2016).

4.5. Huntington tus kab mob

HD yog qhov mob hnyav, ib leeg-gene tsis meej uas cuam tshuam nrog kev hloov pauv hauv CAGtriplicate rov ua dua ntawm qhov pib ntawm exon hauv HTT noob ntawm chromosome 6. Yuav luag 10-35 qhov txawv txav rov ua dua tau txuas rau HD (Ghosh thiab Tabrizi, 2018).

Xws li ib tug noob thaum txhais ua ib tug cytotoxic protein (nyob rau hauv cov ntaub ntawv no Huntingtin) nrog ntev polyglutamine tracts.Nyob rau hauv luv luv, nws muaj peev xwm yuav xaus lus tias tag nrho cov kab mob neurogenerative, nyob rau hauv ib tug los yog lwm txoj kev, yog txuam nrog ntau yam noob thiab yog multifactorial keeb kwm. Cov noob hloov pauv hauv ib tus kab mob tuaj yeem yog qhov txaus ntshai rau lwm tus kab mob.

Raws li qhov tshwm sim, tseem xav tau kev tshawb fawb ntxiv rau kev ua haujlwm ntawm cov noob caj noob ces kom nkag siab txog lub luag haujlwm ntawm cov noob caj ces cuam tshuam rau ND hauv txoj hauv kev zoo dua. Cov noob caj noob ces tau hais los saum no yog luv luv luv hauv Table 1.

5. Polypharmacology

Txhua cov tshuaj molecule muaj nyob rau hauv lub khw muag tshuaj yog ib tug tshuaj compound ua los ntawm ntau heterocyclic scaffoldssubstituted nrog txawv functional pawg.

Cov pab pawg ua haujlwm nrog rau stereochemistry txiav txim siab lub hom phiaj affinity ntawm cov tshuaj molecule. Kev sib cuam tshuam ntawm cov tshuaj-cov phiaj xwm tshwj xeeb ua rau muaj txiaj ntsig zoo thaum tib lub sijhawm, kev sib cuam tshuam ntawm cov tshuaj tsis xav tau yuav ua rau muaj kev phiv loj heev.

Polypharmacology yog ib lo lus dav uas hais txog ib qho tshuaj ua yeeb yam ntawm ntau lub hom phiaj lossis kev sib xyaw ntawm cov tshuaj uas tuaj yeem hloov kho ntau lub hom phiaj ib txhij los daws cov tsos mob ntawm tus kab mob tshwj xeeb (Reddy thiab Zhang, 2013; Jalencasand Mesters, 2013; Albertini li al. , 2020). Txoj kev tshawb nrhiav tshuaj nyob rau xyoo dhau los tau tsom mus rau "ib qho tshuaj-ib lub hom phiaj".

Txawm li cas los xij, qhov tsis ua tiav ntawm ib qho tshuaj tiv thaiv monofunctional los qhia txog cov txiaj ntsig kho mob hauv cov kab mob neurodegenerative nyuaj xws li Alzheimer's thiab Parkinson's yog ua rau maj mam hloov mus rau kev tshawb pom tshuaj polypharmacological.

Tsis tas li ntawd, ntau qhov xwm txheej ntawm ND thiab kev xav paub kom pom qhov ua tau tawm ntawm cov hom phiaj rau cov tshuaj kho mob tam sim no (tshuaj kho mob rov qab) ua haujlwm ntxiv rau kev txhawb nqa kom txav mus rau txoj hauv kev polypharmacological rau kev kho mob ntawm ND.

5.1. Ib qho tshuaj-ntau lub hom phiaj polypharmacological mus kom ze

Cov tshuaj tau muab cais tawm hauv pawg no tseem hu ua ntau lub hom phiaj directedligands (MTDL) lossis tsuas yog ntau lub hom phiaj ligands / tshuaj (Albertini li al.,2020). MTDLs thaum piv rau cov uas twb muaj lawm ib tug monofunctional tsom cov tshuaj muaj peev xwm tsom ntau txoj kev taw qhia nyob rau tib lub sij hawm thiab vim li ntawd, MTDLs qhia ntau dua kev kho mob tau txais kev lees paub vim tias lawv cov kev sib koom ua ke lossis cov txheej txheem ntxiv.

Tsis tas li ntawd, txoj kev pheej hmoo ntawm kev siv tshuaj tiv thaiv los ntawm lwm yam kev siv tshuaj lom neeg thiab kev hloov pauv ntawm cov noob raug txo qis (Van der Schyf, 2011). MTDLs yog lub sij hawm txawv teb chaws thiab tuaj yeem muab faib ntxiv rau hauv 1) Co-ligands thiab 2) Hybridligands.

Ib qho kev sib piv ntawm ob chav kawm ntawm ligands yog qhia hauv daim duab 3. Ob peb MTDLs uas tseem tsis tau pom zoo tab sis yuav qhia tau tias muaj txiaj ntsig zoo hauv ntau yam ND tau tham hauv nqe lus hauv qab no.

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