Kev Txhim Kho Kev Txhim Kho Rau Spinal Muscular Atrophy: Perspectives For Muscular Dystrophies Thiab Neurodegenerative Disorders Part 2

Cellular thiab molecular muaj nuj nqi ntawm SMN

Lub SMN protein yog qhia nyob rau hauv ubiquitously thiab tsis tsuas yog pom nyob rau hauv lub paj hlwb, tshwj xeeb tshaj yog nyob rau hauv motoneurons. SMN ua haujlwm nyob rau hauv cov protein complex uas mediatesspliceosomal snRNP sib dhos [91, 176, 194, 233].

Lub paj hlwb yog ib txoj hauv kev lom neeg uas tswj hwm ntau yam dej num ntawm tib neeg lub cev, suav nrog kev xav, kev ua, thiab kev nco. Txhawm rau txhim kho kev nco, lub paj hlwb kev noj qab haus huv yog qhov tseem ceeb.

Kev sib txuas ntawm lub paj hlwb thiab kev nco yog sawv cev los ntawm cov neurons hauv lub hlwb, uas yog lub luag haujlwm rau kev xa cov ntaub ntawv thiab kev sib txuas hauv lub hlwb. Thaum peb kawm lossis paub txog qee yam, neurons hauv lub hlwb tsim kev sib txuas tshiab, pab peb nco qab cov ntaub ntawv ntxiv.

Tib lub sijhawm, lub paj hlwb kuj tuaj yeem ua lub luag haujlwm tseem ceeb hauv peb txoj kev nco. Lub cim xeeb hauv lub siab yog tsim los ntawm kev sib txuas thiab kev ua haujlwm synchronized ntawm ntau cov neurons. Lub paj hlwb pab peb ntxiv dag zog thiab sib sau ua ke cov kev nco, ua rau lawv muaj zog dua thiab kav ntev.

Txawm li cas los xij, qee cov kab mob neurological tuaj yeem cuam tshuam rau peb lub cim xeeb. Piv txwv li, kev ntxhov siab ntev lossis tsis pw tsaug zog tuaj yeem cuam tshuam kev ua haujlwm ntawm lub paj hlwb thiab ua rau peb lub cim xeeb poob. Yog li ntawd, peb yuav tsum tau ua qee cov kauj ruam ua kom peb lub paj hlwb noj qab haus huv.

Qee yam kev noj qab nyob zoo, xws li pw tsaug zog txaus, kev tawm dag zog kom zoo, thiab noj zaub mov kom zoo, muaj txiaj ntsig zoo rau kev noj qab haus huv ntawm lub paj hlwb. Tsis tas li ntawd, kev nyeem ntawv ntau ntxiv, kawm paub kev paub tshiab ntxiv, thiab nyuaj rau peb tus kheej ntau tuaj yeem txhawb nqa kev ua haujlwm ntawm lub paj hlwb thiab pab peb txhim kho peb lub cim xeeb.

Nyob rau hauv luv luv, kev sib txuas ntawm lub paj hlwb thiab lub cim xeeb yog ze heev, thiab ua kom lub paj hlwb noj qab haus huv yog ib qho tseem ceeb heev rau peb nco. Tsuav yog peb ua raws li kev ntsuas tsim nyog thiab ua kom muaj kev noj qab haus huv thiab ua tiav lub neej, peb yuav muaj kev nco zoo dua. Nws tuaj yeem pom tias peb yuav tsum txhim kho kev nco, thiab Cistanche deserticola tuaj yeem txhim kho kev nco zoo vim Cistanche deserticola yog cov khoom siv tshuaj hauv Suav teb uas muaj ntau yam teebmeem, ib qho ntawm kev txhim kho kev nco. Kev ua tau zoo ntawm Cistanche deserticola los ntawm ntau yam khoom xyaw uas nws muaj, suav nrog tannic acid, polysaccharides, flavonoid glycosides, thiab lwm yam. Cov khoom xyaw no tuaj yeem txhawb lub hlwb kev noj qab haus huv los ntawm ntau txoj hauv kev.

Nyem paub 10 txoj hauv kev los txhim kho kev nco

Classical Smn gene knockout nyob rau hauv nas ua rau thaum ntxov embryoniclethality [264], uas yog raws li lub hauv paus ntawm Smn nyob rau hauv tag nrho cov cell hom raws li ib tug tseem ceeb cellular protein rau pre-mRNA ua.

Cov nas nrog homozygousgene knockout ntawm endogenous Smn nrog 2 daim ntawv theej ntxiv ntawm tib neeg SMN2 txhim kho SMA hnyav, yog li ua raws li SMA hom 1 hauv tib neeg [208].

Txawm li cas los xij, mRNA qib hauv feem ntau ntawm cov nas no suav nrog lub hlwb zoo li qub, thiab kev sib txuas ntawm cov ntawv sau tseg tsis cuam tshuam [140]. Qhov no qhia tau hais tias cov txheej txheem ntawm pre-mRNAs suav nrog kev sib cais feem ntau tsis cuam tshuam rau SMA.

Txawm li cas los xij, nws tsis tuaj yeem raug cais tawm tias ob peb daim ntawv teev npe yuav tsum muaj qib siab ntawm SMN protein thiab SMN complex yog li cov qib SMN uas tuaj yeem tsim los ntawm plaub daim ntawv luam ntawm SMN2 tsis txaus hauv cov hlwb.

Cov kev tshawb fawb hauv Drosophila tau muab pov thawj tias cov ntawv sau tshwj xeeb uas xav tau U11/12 me splice complex tshwm sim muaj kev cuam tshuam rau Smn depletion [132, 177,181] ntau dua li feem ntau ntawm cov ntawv sau uas tau ua tiav ntawm U1, 2, 4, 5, 6- dependent loj spliceosome complex. Txawm li cas los xij, cov kev tshawb pom no tau raug teeb meem los ntawm kev soj ntsuam tias kev loj hlob ntawm Smn-tsis muaj fries, feem ntau, yog qeeb thiab tias U11/12-dependent pre-mRNA splicing thaum lub sij hawm ib txwm loj hlob tshwm sim tsuas yog tom qab larval theem [98].

Yog li, qhov qis dua ntawm U11 / 12 me me splice complex-dependent mRNA kev hloov kho tuaj yeem cuam tshuam qhov kev ncua ntawm kev loj hlob larval hauv Smn-tsis muaj fies. Txawm hais tias U11/12, nrog rau U2-dependentintron retention, tau pom nyob rau hauv cov ntawv sau tseg hauv Smn-tsis muaj yoov thiab nas, tsuas yog qee qhov tau lees paub, xws li TMEM41B/Stasimon thiab Mdm2/4[66, 181, 275 , 300] ib.

Txawm hais tias kev soj ntsuam tias kev kho dua tshiab ntawm Mdm2/4 qhia tau txhim kho lub cev muaj zog rau qee qhov, qhov kev kho dua tshiab ntawm Mdm2/4 tsis muaj txiaj ntsig zoo rau kev ciaj sia ntawm SMA nas [300].

Ib sab ntawm cov khoom ntawm cov classical SMN complex, ntxiv SMN cov koom tes sib koom tes tau raug txheeb xyuas; ntawm lawv hnRNP R [256], TDP-43 [296], FUS [323], thiab HuD[82], uas tau koom nrog ntau lub paj hlwb suav nrog kev tswj hwm kev hloov pauv, nuclear pre-mRNAprocessing, nuclear export thiab subcellular thauj ntawm ntau mRNAs. [4, 18, 81, 82, 102, 104, 110, 218, 255, 325, 326].

Tshwj xeeb, qhov kev hloov pauv ntawm axonal ntawm -actinmRNA cuam tshuam loj heev hauv Smn- [255], hnRNP R-[102], thiab TDP-43- [33] tsis muaj neurons. HnRNP R asan tus khub kev sib raug zoo ntawm SMN muaj nyob rau hauv lub nucleusand lub cytosol, nrog rau axons ntawm motoneurons [68,256]. Nws koom nrog hauv subcellular thauj ntawm mRNAs thiab lwm hom RNA hauv axons [32, 34, 261].

Kev cai ntawm SMN qhia thaum lub sij hawm kev loj hlob

Txoj kev loj hlob ntawm SMN nyob rau hauv nas thiab tib neeg qhia tau hais tias dynamic nta. SMN proteinlevels yog siab thaum lub sij hawm cev xeeb tub thiab poob qis thaum ntxov perinatal theem [20, 38, 97, 140, 144, 240,241].

Hauv cov ntshav, cov qib SMN siab dua yog pom nyob rau hauv cov menyuam yaus piv rau cov neeg laus [309, 330]. Themedian SMN protein theem yog 2.

Qhov no sib txawv nce thaum lub sij hawm kev loj hlob. SMN cov protein ntau yog kwv yees li 6.5-fold txo qis hauv tib neeg cov ntaub so ntswg autopsy (lumbar lossis thoracic qaum qaum) hauv cov tib neeg hnub nyoog 3 hlis txog 14 xyoo [240, 241] thaum piv rau cov theem ntawm fetal theem. SMN theem yog plaub npaug qis hauv tib neeg tus txha caj qaum kuaj los ntawm SMA cov neeg mob tom qab yug me nyuam (txog li 3 lub hlis) hauv kev sib piv rau cov kev noj qab haus huv.

Kev txo qis ntawm qib siab prenatal SMN protein ntau nyob rau theem tom qab yug me nyuam kuj tau pom nyob rau hauv lub frontal cortex, diaphragm, thiab skeletal nqaij [240, 241].SMN protein ntau correlates tsuas yog modestly nrog tag nrho SMN1 thiab SMN2 mRNA transcript theem hauv prenataltissue cov qauv.

Qhov kev poob qis hauv nruab nrab SMN1 tag nrho-ntev SMN2 mRNA qib ntawm cov theem tom qab yug me nyuam thaum ntxov hauv cov ntaub so ntswg los ntawm kev tswj kev noj qab haus huv yog me me piv rau qib protein [240, 241]. Qhov no qhia tau hais tias SMN protein theem poob qis thaum ntxov postnatal theem ywj siab ntawm SMN txhawb kev ua haujlwm [71, 206, 207, 257] ntawm posttranscriptional mechanisms [53, 149]. Hauv cov nas, Smn protein theem poob qis hauv tus txha caj qaum ntawm hnub embryonic (E) 14 thiab 19.

Lub sijhawm no yog ua raws li kev poob qis ntawm hnub tom qab yug menyuam (P) 5 thiab 15 [140]. Tam sim no, cov txheej txheem tswj hwm SMN qhia ntawm qib posttranscriptional thiab posttranslational tsis tau daws tag nrho. Ob leeg, kev tswj kev txhais lus thiab kev tswj hwm ntawm Smn protein degradation tuaj yeem ua lub luag haujlwm.

Lub instability ntawm SMNΔ7 protein yog kho los ntawm ib tug degradation signaltermed degron (SMNΔ7-DEG) uas yog tsim los ntawm cov tshiab C-terminus nyob rau hauv lub truncated protein los ntawm SMN2gene [45]. Inactivation ntawm SMNΔ7-DEG los ntawm ib qho kev hloov pauv hloov pauv stabilizes SMNΔ7, uas nyob rau hauv lem tuaj yeem them rau SMN poob hauv cov kab ntawm tes.

SMA: motoneuron thiab neuromuscular pathology

Raws li tau hais ua ntej, cov txheeb ze SMN cov protein ntau yog qhov siab tshaj plaws ntawm kev ua menyuam yaus hauv tib neeg thiab hauv cov nas (1 lub lis piam ua ntej yug menyuam) [140, 240, 241] implying lub luag haujlwm tseem ceeb ntawm SMN incellular sib txawv. Nyob rau hauv motoneurons, lub sij hawm no ntawm high SMN protein ntau coincides nrog rau theem kev loj hlob thaum cov neurons loj hlob tawm axons thiab formsynaptic tiv tauj nrog skeletal / striated nqaij fibers los tsim neuromuscular endplates.

Cov kev tshawb pom no qhia tias cov protein ntau ntawm SMN yog qhov tsim nyog rau kev txhim kho ntawm cov kab mob neuromuscular [38,140, ​​141]. Thaum ntxov ua ntej yug me nyuam, kwv yees li ib nrab ntawm cov postmitotic motoneurons uas tau pib tsim nyob rau hauv tus txha caj qaum undergo physiological cell tuag. Kev loj hlob ntawm tes tuag yog tswj los ntawm cov xwm txheej neurotrophic [11, 116, 129, 234, 265, 266, 268].

Hauv tib neeg thiab hauv cov nas, SMN tsis muaj peev xwm tsis ua kom lub motoneuron poob rau lub sijhawm tseem ceeb ntawm kev loj hlob no. Lub sijhawm kev loj hlob ntawm lub cev motoneuron kev tuag yog ua raws li synapses raug tshem tawm thaum cov synapses supernumerary raug tshem tawm [173] kom ib leeg nqaij fiber ntau tau txais synapticinput los ntawm ib qho motoneuron nkaus xwb.

Lub sij hawm no lub qhov rais ofpolysynaptic tshem tawm coincides nrog lub deterioration ntawm lub cev muaj nuj nqi thiab motoneuron degeneration yam tsawg kawg hauv nas qauv ntawm SMA hom 1 thiab 2 [103, 126, 166].Lub sij hawm no theem, txog 17-29% ntawm motoneurons yog lostin SMA hom 1 nas qauv. piv rau cov neeg noj qab nyob zoo [208]. Motoneuron poob txuas ntxiv tom qab cov theem postnatal no. Hauv cov nas heterozygous Smn uas tsuas yog ib qho allele ntawm Smn raug tshem tawm, uas ua rau txo qis ntawm 50% ntawm Smn protein ntau ntau, txog 50% ntawm motoneurons poob rau theem ntawm 12 lub hlis [140, 274].

Ib yam li ntawd hauv cov menyuam yaus uas muaj SMA hom 1, motoneuronloss hnyav tau raug pom nyob rau theem kawg. Thaum muaj hnub nyoog 5-22 lub hlis, motoneuron poob rau cov neeg mob hom 1SMA nce mus rau ntau dua 70% [272].Thaum motoneurons raug cais tawm ntawm embryonicSmn−/−; SMN2 nas thiab kab lis kev cai rau lub sijhawm mus txog 7 hnub, kev tuag ntawm tes tsis tau txhim kho tab sis axon txuas ntxiv tau hloov pauv ntau.

Qhov no axonal defect [139, 156, 255] tshwm sim raws li ib qho tseem ceeb feature thiab tseem pom nyob rau hauv lwm yam Smn-deficient tsiaj qauv xws li zebrafish [192, 317]. Kev loj hlob tsis zoo axon cuam tshuam nrog txo qis actin dynamics [211, 255] thiab hloov pauv excitability los ntawm voltage-gated Ca2+ channels [139].

Kev kho mob ntawm SMA thiab tswj cov nas nrog calcium channelmodulator R-Roscovitine ua rau muaj coob tus khaws cia thiab txawm tias rov tsim kho cov kab mob neuromuscular junctions (NMJs) [291]. Yog li, kev ua haujlwm tsis zoo ntawm presynaptic thiab txo qis kev tso tawm tso tawm ua rau muaj kev cuam tshuam rau cov kab mob thiab degeneration ntawm neuromuscular junctionsand axons hauv SMA.

Ib qho kev tshwm sim thiab cov yam ntxwv ntawm cov kab mob ntawm SMA yog tias cov leeg mob sib thooj tshwm sim ntau dua li cov leeg nqaij. Piv txwv li, cov leeg nqaij forfinger txav tau tshwm sim tsawg dua li cov leeg trapezius, deltoid, quadriceps, lossis gastrocnemius nqaij [69]. Qhov no tshwm sim thawj zaug pom qhov tsis txaus ntseeg vim tias motoneurons nrog ntev axons feem ntau suav tias yog qhov muaj kev phom sij ntau dua li cov uas muaj luv axons. Txawm li cas los xij, motoneurons uas innervate cov leeg nqaij rau kev tswj xyuas feem ntau tsim cov cav loj loj nrog lub cev muaj zog axons mus txog ntau txhiab terminals.

Nyob rau hauv sib piv, lub cev muaj zog units rau zoo txav ntawm cov ntiv tes los yog posture feem ntau me me. Piv txwv li, lub cev muaj zog unitin ntiv tes cov leeg xws li thawj lumbrical leeg yog nyob rau hauv ntau ntawm 100 [84, 115]. Nyob rau hauv sib piv, lub gastrocnemiusmuscle muaj ib tug innervation piv ntawm 1000-2000 nqaij fibers ib motoneuron [84]. Yog li, qhov tsis zoo ntawm motoneurons hauv SMA zoo li cuam tshuam nrog qhov loj ntawm motorunits. Axons ntawm motoneurons muaj cov qib siab ntawm mRNAs uas tau thauj mus rau hauv cov kab mob ntawm cov hlab ntsha no, uas lawv tau txhais hauv zos [34, 220, 261].

Cov ntawv teev lus encoding actin, mitochondrial proteins los yog cov khoom ntawm presynaptic activezones yog enriched nyob rau hauv lub cev muaj zog axons. Kev thauj mus los ntawm cov ntawv sau no zoo li muaj kev ntxhov siab heev hauv Smndefcient motoneurons [34, 211, 261].

Rau qee qhov, kev hloov pauv tsis raug ntawm cov ntawv sau tseg rau cov proteins zoo li tau them nyiaj rau hauv motoneurons nrog cov ceg qis ntawm cov ceg axonal thiab cov lej qis ntawm cov neuromuscular junctions uas tau txais kev pabcuam los ntawm cov ceg ntoo.

Txawm li cas los xij, hauv motoneurons ntawm lub cev muaj zog loj xws li cov txheej txheem them nyiaj yuav raug txwv, thiab tej zaum yuav ua rau degeneration ntawm presynaptic compartments thiab retrograde degeneration ntawm axons.

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