Emerging Me-molecule Therapeutic Approaches Rau Alzheimer's Disease Thiab Parkinson's Disease Raws Li Lub Hom Phiaj MicroRNAs

Lub luag haujlwm ntawm microRNAs hauv kev loj hlob ntawm cov kab mob neurodegenerative: MicroRNAs (miRNAs) yog endogenous, non-coding, thiab luv RNA nucleotides uas tswj cov noob qhia los ntawm kev sib koom ua ke nrog cov neeg xa xov xwm RNA (mRNA) ntawm thaj tsam 3′ untranslated (3′. UTR). Yog li, miRNAs ua lub luag haujlwm tseem ceeb hauv kev inhibition lossis degradation ntawm messenger RNAs (Gebert thiab MacRae, 2019). Ob lub ribonucleases (RNase) III enzymes tswj cov biogenesis ntawm miRNAs; Drosha thiab Dicer. Thawj kauj ruam hauv biogenesis suav nrog kev sib cais ntawm thawj miRNAs (pri-miRNAs) hauv lub cell nucleus los ntawm Drosha, uas ua rau tsim cov qia luv-voj pre-miRNAs. Tom qab ntawd, cov pre-miRNAs no raug thauj mus rau cytoplasm thiab ua tiav los ntawm Dicer ua rau cov miRNAs paub tab (O'Brien li al., 2018).

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Ntau cov kab mob ua rau pom qhov txawv txav ntawm miRNAs, xws li mob cancer mis, leukemia, hepatocellular carcinoma, thiab kab mob plawv thiab neurodegenerative. Ntau tshaj 2000 miRNAs tau raug txheeb xyuas kom muaj lub luag haujlwm tseem ceeb hauv kev sib txawv ntawm cov neurons, uas qhia txog kev koom tes ntawm miRNAs hauv cov txheej txheem neuronal sib txawv. Cov ntaub ntawv nthuav tawm tias miRNAs cuam tshuam rau ntau txoj hauv kev uas cuam tshuam ncaj qha rau kev loj hlob ntawm cov kab mob neurodegenerative (Daim duab 1A). -Synuclein, ib qho presynaptic protein cuam tshuam rau hauv cov kab mob neurological, yog cov protein tsis txaus ntseeg hauv lub cev. Kev sib sau ua ke ntawm -synuclein los tsim cov fibrils insoluble thiab Lewy lub cev yog ib qho tseem ceeb ntawm cov kab mob pathological rau kev kuaj mob ntawm lub paj hlwb, xws li Parkinson's disease thiab Alzheimer's disease. Kev sib sau ntawm -synuclein hauv tib neeg cov hlwb neuroblastoma yog txhawb nqa los ntawm miR-16-1, uas yog vim muaj peev xwm ntawm miR-16-1 kom txo qis cov protein ua kom sov 70. Tsis ntev los no, lub peev xwm ntawm miR-153 kev tswj tsis zoo -synuclein tau pom nyob rau hauv cov nas parkinsonian (Cressatti li al., 2019).

Ntxiv mus, qhov inhibition ntawm miR-34b nyob rau hauv cov neeg mob uas muaj tus kab mob Parkinson txhim kho qhov kev qhia ntawm -synuclein nyob rau hauv tib neeg lub hlwb. Tau, ib qho microtubule-txuas nrog cov protein, yog qhia nyob rau hauv tib neeg lub hlwb paub tab nyob rau hauv rau isoforms. Qhov txawv txav ntawm hyperphosphorylation thiab sib sau ua ke ntawm tau mus rau hauv cov laus fibrils tau pom nyob rau hauv Alzheimer's kab mob nrog rau lwm yam kab mob neurological, hu ua tauopathies. Downregulation ntawm miR-212 thiab miR-132 tau kuaj pom hauv neurally derived plasma exosomes ntawm cov neeg mob Alzheimer's disease (Cha et al., 2019). Raws li cov kev tshawb pom no, kev ntsuam xyuas ntawm cov theem ntawm miR212 thiab miR-132 nyob rau hauv cov hlab ntsha extracellular yog suav tias yog ib qho kev cog lus rau kev kuaj mob rau Alzheimer's disease. Ntau cov ntawv tshaj tawm tau pom tias muaj kev sib koom ua ke ntawm cov kab mob neurodegenerative thiab kev ua haujlwm tsis zoo hauv mitochondrial dynamics, xws li kev hloov pauv hauv mitochondria loj, hloov cov duab, fission-fusion, thiab mitochondria zog). Hauv cov ntsiab lus no, miR-27a tau raug tshaj tawm los txwv kev qhia ntawm PTEN-induced putative kinase 1, mitochondrial serine / threonine kinase, uas yog ib qho tseem ceeb hauv mitophagy. Yog li, miR-27 ua lub luag haujlwm tseem ceeb hauv kev tswj cov autophagic clearance ntawm puas mitochondria.

Kev hloov pauv hauv PTENinduced putative kinase 1 yog suav tias yog ib qho tseem ceeb ntawm kev ua rau autosomal recessive Parkinson tus kab mob. Raws li cov kab no, miR-494 induces mitochondrial puas thiab oxidative stress-induced neuronal puas los ntawm kev txo qis kev qhia ntawm Parkinson tus kab mob protein 7, ib tug inhibitor ntawm aggregation ntawm -synuclein (Catanesi li al., 2020). Tsis tas li ntawd, tshiab miR-455- 3p tau qhia txog kev tiv thaiv kev tiv thaiv ntawm amyloid aggregation los ntawm kev tswj cov kev qhia ntawm mitochondrial fission proteins thiab tswj mitochondrial dynamics (Kumar li al., 2019). Ntau xyoo dhau los, -secretase 1 (BACE1) tau txais kev saib xyuas ntau ntxiv raws li lub hom phiaj kho mob tseem ceeb rau Alzheimer's disease. BACE-1, tseem hu ua -site amyloid precursor protein cleaving enzyme 1, yog qhov tseem ceeb secretase koom nrog hauv kev tsim cov amyloid-peptides hauv tib neeg lub hlwb. Tom qab sib sau ua ke thiab fibrillization ntawm cov peptides los tsim cov plaques amyloid yog cov yam ntxwv tseem ceeb ntawm Alzheimer's disease.

Tsis tas li ntawd, ntau cov ntaub ntawv pov thawj tau pom tias muaj kev cuam tshuam ntawm neurotoxicity ntawm me me oligomers ntawm amyloid-peptides. MiR-298 tsis ntev los no tau raug txheeb xyuas tias yog tus neeg tawm tsam ntawm BACE1 hauv tib neeg kab lis kev cai kab lis kev cai kab lis kev cai nthuav tawm cov peev txheej kho mob ntawm miR298 rau cov kab mob neurodegenerative (Chopra li al., 2020). Ntxiv mus, qhov kev qhia ntawm BACE-1 yog tswj ncaj qha los ntawm miR15b, uas ua haujlwm los ntawm kev tsom mus rau BACE1 mRNA 3′-UTR (Gong et al., 2017). Cov kev tshawb pom no qhia tau hais tias miRNAs yog cov tseem ceeb hauv kev tswj hwm kev ua haujlwm ntawm BACE-1 thiab nws lub luag haujlwm hauv kev tsim cov kab mob neurodegenerative.

Kev loj hlob ntawm me me molecules rau cov kab mob neurodegenerative raws li lub hom phiaj miRNAs:

Kev tsom mus rau cov kab mob ua rau miRNAs nrog cov molecules me me tau nthuav tawm cov txiaj ntsig tau zoo hauv vitro thiab hauv vivo kev tshuaj ntsuam. Yog li, kev siv zog tshawb fawb ntau tau raug coj mus rau kev txhim kho cov tswv yim tshiab rau kev txheeb xyuas thiab tsim cov molecules me me nrog lub peev xwm miRNA khi. Txawm li cas los xij, qhov luv luv ntawm miRNAs tau cuam tshuam qhov kev txheeb xyuas ntawm cov khoom muaj zog me me-molecule binders thiab hloov qhov kev tsom mus rau kev tsom mus rau lub hom phiaj ua ntej-miRNAs nrog cov ntu ntev dua. Inforna thiab Inforna 2.0 yog cov cuab yeej tsim los txheeb xyuas cov molecules me me tsom rau cov qauv RNAs. Cov txheej txheem no yog ua raws li mining motifs (secondary structures) ntawm RNAs raws li lawv cov sequences.

Cov motifs no ces muab piv rau cov ntaub ntawv uas paub RNA motif-me me molecule binding cov neeg koom tes. Inforna ces tshaj tawm cov motif hauv cov ntaub ntawv nrog rau lub hom phiaj RNA. Informa tau siv tsis ntev los no hauv kev txheeb xyuas qhov sib xyaw 1 (Daim duab 1B) ua ib qho inhibitor ntawm -synuclein qhia (Zhang li al., 2020). Compound 1 tsom rau -synuclein mRNA 5′ UTR thiab txo cov theem ntawm a-synuclein los ntawm kev txo qis ntawm SNCA mRNA loaded rau hauv polysomes. Tsis ntev los no, RIBOTACs (ribonuclease targeting chimeras) tau hloov zuj zus raws li chav kawm tshiab ntawm cov khoom me me uas tuaj yeem tsom cov chav RNA sib txawv, suav nrog miRNAs thiab mRNAs (Dey thiab Jaffrey, 2019). Kev tsim ntawm RIBOTACs yog ua raws li kev sib txuas ntawm RNA-binding molecules rau ib qho me me molecule uas ua rau RNA L, ib qho latent ribonuclease, uas ua rau qhov degradation ntawm lub hom phiaj RNA.

Multitargeted directed ligands (MTDLs) rau cov kab mob neurodegenerative tsom rau miRNAs:

MTDLs yog ligands uas tau tsim los cuam tshuam nrog ntau txoj hauv kev koom nrog kev loj hlob ntawm cov kab mob hauv lub paj hlwb vim tias lawv cov yam ntxwv sib txawv. Kev ua tiav zoo kawg nkaus ntawm MTLDs hauv kev txheeb xyuas cov molecules me me nrog rau hauv vitro thiab hauv vivo kev ua tau zoo hauv cov qauv ntawm cov kab mob neurodegenerative tau ua rau muaj kev siv zog txuas ntxiv hauv kev tsim cov cuab yeej tshiab rau kev tsim MTDLs. Hauv cov ntsiab lus no, lub tswv yim tshiab rau kev txheeb xyuas MTDLs rau cov kab mob neurodegenerative tsis ntev los no tau tshaj tawm, uas yog ua raws li kev txwv ob ntawm acetylcholinesterase thiab biogenesis ntawm miRNAs (Gabr thiab Brogi, 2020). Compound 2 (Daim duab 1B), ib tug dual inhibitor ntawm acetylcholinesterase thiab biogenesis ntawm miR-15b, tau ntau npaum li donepezil thiab anti-miR-15 hauv kev tiv thaiv SH-SY5Y neuroblastoma hlwb los ntawm amyloid-beta induced cytotoxicity .

Ntxiv mus, dual inhibition ntawm tau oligomerization thiab biogenesis ntawm miRNAs cuam tshuam rau kev loj hlob ntawm cov kab mob hauv lub paj hlwb (xws li miRNA-146a) tau tshaj tawm tias yog lub tswv yim zoo rau kev tsim MTDLs (Gabr thiab Barbault, 2020). Qhov tshwm sim ntawm qhov kev qhia no tau muab cov khoom sib txuas 3 (Daim duab 1B) uas muaj cov haujlwm zoo tshaj plaws ntawm cov neuroprotective rau miRNA146a antagomir thiab MK-886, ib qho inhibitor ntawm tau aggregation. Cov kev tshawb fawb no qhia ntxiv tias qhov kev tsim ntawm MTDLs tsom rau inhibition ntawm biogenesis ntawm miRNAs tau qhia qhov kev nyiam kho mob profile piv rau kev kho mob monotargeted. Yog li ntawd, kev tshuaj xyuas ntxiv ntawm cov txiaj ntsig ntawm cov txheej txheem no siv hauv vivo qauv ntawm cov kab mob neurodegenerative yuav yog qhov tseem ceeb rau kev txhim kho yav tom ntej.

Cov lus qhia yav tom ntej:

Kev txhim kho cov tswv yim zoo los txheeb xyuas cov molecules me me uas tuaj yeem xaiv khi miRNAs yuav muaj txiaj ntsig zoo rau kev muaj peev xwm los tswj cov kev qhia ntawm cov protein cuam tshuam hauv cov kab mob neurodegenerative. Me me molecule inhibitors ntawm Drosha thiab Dicer tau kawm ntau yam los ua cov cuab yeej los inhibit biogenesis ntawm miRNAs. Txawm li cas los xij, ntau tus inhibitors ntawm Dicer thiab Drosha nthuav tawm txo qis miRNA binding affinity nyob rau hauv lub cellular ib puag ncig thiab tsis muaj peev xwm los thaiv miRNA maturation.

Cov txiaj ntsig no tau raug ntaus nqi los ntawm lub hom phiaj ntawm cov me me molecules nrog rau lawv cov kev sib tw nrog lwm cov macromolecules hauv kev khi miRNAs. Yog li ntawd, kev tsim cov txheej txheem tshiab rau kev xaiv khi ntawm miRNAs yog qhov xav tau heev. Kinetic target guided synthesis (KTGS) yog ib qho kev tshawb nrhiav tshuaj nyob rau hauv qhov chaw uas lub hom phiaj lom neeg xaiv nws cov ligands bidentate los ntawm kev sib sau ua ke los ntawm lub pas dej ntawm cov khoom me me.

Nyob rau hauv KTGS, lub hom phiaj lom neeg ua kom covalent daim ntawv cog lus tsim ntawm lub tsev thaiv nrog cov pab pawg ua haujlwm ua haujlwm ntxiv los ntawm kev txhim kho lub sijhawm resonance. Tom qab dissociation ntawm lub hom phiaj, KTGS hits tuaj yeem kuaj pom hauv xov xwm los ntawm Liquid chromatography-mass spectrometry. Ib txoj hauv kev muaj peev xwm rau kev txheeb xyuas cov kev xaiv binders ntawm miRNAs yuav yog siv KTGS los txheeb xyuas cov molecule me me ntawm lub hom phiaj miRNA.

Cov ntaub ntawv

Catanesi M, D'Angelo M, Tupone MG, Benedetti E, Giordano A, Castelli V, Cimini A (2020) MicroRNAs dysregulation thiab mitochondrial dysfunction nyob rau hauv cov kab mob neurodegenerative. Int J Mol Sci 21:5986.

Cha DJ, Mengel D, Mustapic M, Liu W, Selkoe DJ, Kapogiannis D, Galasko D, Rissman RA, Bennett DA, Walsh DM (2019) miR-212 thiab miR-132 yog downregulated nyob rau hauv neurally derived plasma exosomes ntawm Alzheimer's cov neeg mob. Pem Hauv Ntej Neurosci 13: 1208.

Chopra N, Wang R, Maloney B, Nho K, Beck JS, Pourshafie N, Niculescu A, Saykin AJ, Rinaldi C, Counts SE, Lahiri DK (2020) MicroRNA-298 txo cov theem ntawm tib neeg amyloid-precursor protein ( APP), -site APP converting enzyme 1 (BACE1) thiab tshwj xeeb tau protein moieties.

Mol Psychiatry doi:10.1038/s41380-019- 0610-2.

Cha D, Mengel D, Mustapic M, Liu W, Selkoe D, Kapogiannis D, Galasko D, Rissman R, Gong G, An F, Wang Y, Bian M, Yu LJ, Wei C (2017) miR-15 b represses BACE1 qhia nyob rau hauv sporadic Alzheimer's kab mob. Oncotarget 8:91551-91557.

Cressatti M, Song W, Turk AZ, Garabed LR, Benchaya JA, Galindez C, Liberman A, Schipper HM (2019) Glial HMOX1 qhia txhawb nqa nruab nrab thiab peripheral -synuclein dysregulation thiab pathogenicity nyob rau hauv parkinsonian nas. Glia 67:1730-1744.

Dey SK, Jaffrey SR (2019) RIBOTACs: Me me molecule phiaj RNA rau degradation. Cell Chem Biol 26:1047-1049.

Kumar S, Reddy AP, Yin X, Reddy PH (2019) Novel microRNA-455-3p thiab nws cov txiaj ntsig tiv thaiv kev ua haujlwm tsis zoo ntawm APP thiab amyloid beta toxicity hauv Alzheimer's disease. Biochem Biophys Acta Mol Basis Dis 1865:2428-2440.

O'Brien J, Hayder H, Zayed Y, Peng C (2018) Txheej txheem cej luam ntawm microRNA biogenesis, cov txheej txheem ntawm kev ua, thiab kev ncig. Pem hauv ntej Endocrinol 9:402.

Gabr MT, Barbault F (2020) Thawj dual binder ntawm microRNA146a thiab monomeric tau: Ib txoj hauv kev tshiab rau ntau hom kev kho mob rau cov kab mob neurodegenerative. Chem Commun 56:9695-9698.

Gabr MT, Brogi S (2020) MicroRNA-based multitarget mus kom ze rau Alzheimer's disease: Tshawb nrhiav thawj zaug hauv chav kawm dual inhibitor ntawm acetylcholinesterase thiab micro-RNA-15b biogenesis. J Med Chem 63:9695- 9704.

Gebert LFR, MacRae IJ (2019) Kev tswj hwm ntawm microRNA muaj nuj nqi hauv cov tsiaj. Nat Rev Mol Cell Biol 20:21-37.

Zhang P, Park HJ, Zhang J, Junn E, Andrews RJ, Velagapudi SP, Abegg D, Vishnu K, Costales MG, Childs-Disney JL, Adibekian A, Moss WN, Mouradian MM, Disney MD (2020) Kev txhais lus ntawm intrinsically tsis meej protein a-synuclein yog inhibited los ntawm ib tug me me molecule tsom nws cov qauv

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