SNCA
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Alfa-sinuklein jest protein koji je kod ljudi kodiran genom SNCA sa hromosoma 21.[1] Alfa-sinuklein je neuronski protein koji reguliše sinapsni vezikulski promet i naknadno oslobađanje neurotransmitera.
Ima ga u izobilju u mozgu, dok se manje količine nalaze u srcu, mišićima i drugim tkivima. U mozgu, alfa-sinuklein nalazi se uglavnom u aksonskim terminalima presinapsnih neurona.[1] Unutar ovih terminala, alfa-sinuklein stupa u interakciju sa fosfolipididima.[2] and proteins.[1][3][4] Presinapsnii terminali oslobađaju hemijske glasnike, zvane neurotransmiteri, iz odjeljaka poznatih kao sinapsne vezikule. Oslobađanje neurotransmitera prenosi signale između neurona i ključno je za normalnu funkciju mozga.[1]
Ljudski alfa-sinuklein protein sastoji se od 140 aminokiselina.[5][6][7] Fragment alfa-sinukleina, poznat kao ne-Abeta komponenta (NAC) amiloida Alzhemerove bolesti, prvobitno pronađen u frakciji obogaćenoj amiloidom, pokazao se kao fragment njegovog prekursorskog proteina, NACP.[5] Kasnije je utvrđeno da je NACP ljudski homolog sinukleina u rodu Torpedo. Stoga se NACP sada naziva ljudski alfa-sinuklein.[8]
Tkivna ekspresija
[uredi | uredi izvor]Alfa-sinuklein je sinukleinski protein nepoznate funkcije koji se prvenstveno nalazi u nervnom tkivu, čineći čak jedan posto svih proteina u citosolu moždanih ćelija.[9] To je pretežno neuronski protein eksprimiran u neokorteksu, hipokampusu, substantia nigra, talamusu i cerebellumu, ali se može naći i u neneuronskim ćrlijama glije.[10] Kod melanocita ekspresija SNCA proteina može biti regulirana transkripcijskim faktorom povezanim s mikroftalmijom (MITF).[11]
Utvrđeno je da je alfa-sinuklein u velikoj mjeri lokaliziran u jedru moždanih ]neurona sisara, što ukazuje na ulogu alfa-sinukleina u jedru.[12] Međutim, sinuklein se uglavnom nalazi na presinapsnim krajevima, u slobodnom ili membranom vezanom obliku,[13] pri čemu je otprilike 15% sinukleina vezano za membranu u bilo kojem periodu u neuronima.[14]
Takođe je pokazano da je alfa-sinuklein lokalizovan u neuronskim mitohondrijama.[15][16] Alfa-sinuklein je visoko eksprimiran u mitohondrijama olfaktornih režnjeva, hipokampusu, strijatumu i talamusu, gdje je citosolni alfa-sinuklein također bogat. Međutim, moždana kora i mali mozak su dva izuzetka, koji sadrže bogat citosolni alfa-sinuklein, ali vrlo niske nivoe mitohondrijskog alfa-sinukleina. Pokazalo se da se alfa-sinuklein nalazi u unutrašnjoj membrani mitohondrija, te da je inhibitorni efekat alfa-sinukleina na kompleks I, aktivnosti mitohondrijskog respiratornog lanca ovbisne od doze. Stoga se sugerira da je alfa-sinuklein u mitohondrijama različito eksprimiran u različitim regijama mozga, a pozadinski nivoi mitohondrijskog alfa-sinukleina mogu biti potencijalni faktor koji utiče na funkciju mitohondrija i predisponira neke neurone na degeneraciju.[16]
Najmanje tri izoforme sinukleina proizvode se alternativnom preradom.[17] Najveći oblik proteina, i onaj koji se najviše istražuje, je protein pune dužine od 140 aminokiselina. Druge izoforme su alfa-sinuklein-126, kojem nedostaju ostaci 41-54 zbog gubitka egzona 3 i alfa-sinuklein-112,[18] kojem nedostaju ostataci 103 –130 zbog gubitka egzona 5.[17]
Aminokiselinska sekvenca
[uredi | uredi izvor]Dužina polipeptidnog lanca je 140 aminokiselina, a molekulska težina 14.460 Da.
10 | 20 | 30 | 40 | 50 | ||||
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MDVFMKGLSK | AKEGVVAAAE | KTKQGVAEAA | GKTKEGVLYV | GSKTKEGVVH | ||||
GVATVAEKTK | EQVTNVGGAV | VTGVTAVAQK | TVEGAGSIAA | ATGFVKKDQL | ||||
GKNEEGAPQE | GILEDMPVDP | DNEAYEMPSE | EGYQDYEPEA |
Struktura
[uredi | uredi izvor]Alfa-sinuklein u rastvoru smatra se unutrašnje poremećenim proteinom, tj. nedostaje mu jedna stabilna 3D struktura.[19][20] Od 2014. godine, sve veći broj izvještaja sugerira, međutim, prisustvo parcijalnih struktura ili uglavnom strukturiranih oligomernih stanja u strukturi rastvora alfa-sinukleina čak i u odsustvu lipida. Ovaj trend je također podržan velikim brojem mjerenja pojedinačnih molekula (optičkom pincetom) na pojedinačnim kopijama monomernog alfa-sinukleina, kao i kovalentno pojačanih dimera ili tetramera alfa-sinukleina.[21]
Alfa-sinuklein je specifično je naviše regulirana u diskretnoj populaciji presinapsnih terminala mozga tokom perioda sinapsnog preuređivanja vezanog za akviziciju.[22] It has been shown that alpha-synuclein significantly interacts with tubulin,[23] i da alfa-sinuklein može imati aktivnost kao potencijalni protein povezan sa mikrotubulama, kao što je tau.[24] Dokazi sugeriraju da alfa-sinuklein funkcionira kao molekulski prattelj u formiranju kompleksa SNARE.[25][26] Konkretno, istovremeno se vezuje za fosfolipide plazmamembrana preko svog N-terminalnog domena i za sinaptobrevin-2, preko svog C-terminalnog domena, sa povećanim značajem tokom sinapsne aktivnosti.[27] Ustvari, sve je više dokaza da je alfa-sinuklein uključen u funkcionisanje neuronskog Golgijevog aparata i prometu vezikula.[28]
Pokazalo se da alfa-sinuklein značajno interraguje sa tubulinom,[23] i da alfa-sinuklein može imati aktivnost kao potencijalni protein povezan sa mikrotubulama, kao tau.[24]
Navodno je alfa-sinuklein neophodan za normalan razvoj kognitivnih funkcija. Nokaut-miševi s ciljanom inaktivacijom ekspresije alfa-sinukleina pokazuju narušeno prostorno učenje i radno pamćenje.[29]
Funkcija
[uredi | uredi izvor]Iako funkcija alfa-sinukleina nije dobro shvaćena, studije sugeriraju da on ima ulogu u ograničavanju mobilnosti sinapsnih vezikula, posljedično prigušujući recikliranje sinapsnih vezikula i oslobađanje neurotransmitera.[3][30][31][32][33][34][35]
Alternativno mišljenje je da se alfa-sinuklein vezuje za VAMP2 (sinaptobrevin) i stabilizuje SNARE komplekse;[27][36][37][38][39] iako nedavne studije pokazuju da je vezivanje alfa-sinukleina-VAMP2 ključno za alfa-sinuklein-posredovanu atenuaciju reciklaže sinapsnih vezikula, povezujući dva naizgled divergentna pogleda.[3] Također može pomoći u reguliranju oslobađanja dopamina, tipa neurotransmitera koji je kritičan za kontrolu početka i zaustavljanja voljnih i nevoljnih pokreta.[1]
Alfa-sinuklein modulira procese popravama DNK , uključujući popravku dvolančanih prekida (DSB).[40] Markeri odgovora na oštećenje DNK kolokalizuju se sa alfa-sinukleinom da formiraju diskretna žarišta u ljudskim ćelijama i mišjeg mozga. Smanjenje alfa-sinukleina u ljudskim ćelijama uzrokuje povećano uvođenje DNK DSB-a, nakon izlaganja bleomicinu i smanjenu sposobnost popravljanja ovih DSB-a. Osim toga, alfa-sinuklein nokaut-miševa pokazuje viši nivo DSB-a, a ovaj problem se može ublažiti transgenim ponovnim uvođenjem ljudskog alfa-sinukleina. Alfa-sinuklein promovira put popravke DSB-a koji se naziva nehomologno spajanje krajeva.[40] Čini se da je funkcija popravke DNK alfa-sinukleina ugrožena u Lewijevom tijelu neurona koji nose inkluziju , a to može izazvati ćelijsku smrt.
Sekvenca
[uredi | uredi izvor]Alfa-sinukleinska primarna struktura dijeli se obično u tri različita domena:
- Ostaci 1–60: amfipatski N-terminalni region kojim dominiraju četiri ponavljanja sa 11 ostataka uključujući konsenzusnu sekvencu KTKEGV. Ova sekvenca ima strukturnu alfa-heliksa sklonost sličnu domenima koji vežu apolipoproteine.[41] To je visoko konzervirani terminal koji je u interakciji sa kiselim lipidnim membranama, a sve otkrivene tačkaste mutacije SNCA gena nalaze se unutar ovog terminala.[42]
- Ostaci 61–95: Centralna hidrofobna regija koja uključuje regiju neamiloid-β komponente (NAC), uključenu u agregaciju proteina.[5] Ovaj domen je jedinstven za alfa-sinuklein u porodici sinukleina.[43]
- Ostaci 96–140: visoko kisela i prolinom bogata regija koja nema izrazitu strukturnu sklonost. Ovaj domen ima važnu ulogu u funkciji, rastvorljivosti i interakciji alfa-sinukleina sa drugim proteinima.[27][44]
Klinički značaj
[uredi | uredi izvor]Klasično smatran nestrukturitani protein rastvorljivi, nemutirani α-sinuklein formira stabilno savijeni tetramer koji se opire agregaciji.[45] Ovo zapažanje, iako je reprodukovano i prošireno u nekoliko laboratorija,[46][47][48] još uvijek je predmet debate na terenu zbog oprečnih izvještaja.[49][50][51] Ipak, alfa-sinuklein se agregira i formira nerastvorljiva vlakna u patološkim stanjima koja karakteriziraju Lewyjeva tijela, kao što su Parkinsonova bolest, demencija s Lewyjevim telima i atrofija višestrukih sistema.[52][53] Ovi poremećaji su poznati kao sinukleinopatije. In vitro modeli sinukleinopatija otkrili su da agregacija alfa-sinukleina može dovesti do različitih ćelijskih poremećaja, uključujući oštećenje mikrotubula, sinapsne i mitohondrijske disfunkcije, oksidativni stres, kao i disregulaciju signalizacije kalcija, proteasomskog i lizosomskog puta.[54] Alfa-sinuklein je strukturna komponenta fibrila Lewyjevog tijela. Povremeno, Lewyjeva tijela sadrže tau protein;[55] međutim, alfa-sinuklein i tau čine dva karakteristična podskupa filamenata u istim inkluzivnim tijelima.[56] Patologija alfa-sinukleina se također javlja u sporadičnim i porodičnim slučajevima s Alzheimerovom bolešću.[57]
Mehanizam agregacije alfa-sinukleina je neizvjestan. Postoje dokazi o strukturiranom međuproduktu bogatom beta strukturom koji može biti prethodnik agregacije i, konačno, Lewyjevih tijela.[58] Studija o jednj molekuli iz 2008. sugerira da alfa-sinuklein postoji kao mješavina nestrukturiranih, alfa-heliksa i beta-listova bogatih konformerama u ravnoteži. Mutacije ili uvjeti pufera za koje se zna da poboljšavaju agregaciju snažno povećavaju skupinu beta konformera, što sugerira da bi ovo mogla biti konformacija povezana s patogenom agregacijom.[59] Jedna teorija je da se većina agregata alfa-sinukleina nalazi u presinapsi kao manje naslage što uzrokuje disfunkciju sinapsi.[60] Među strategijama za liječenje sinukleinopatija su spojevi koji inhibiraju agregaciju alfa-sinukleina. Pokazalo se da mala molekula kuminaldehida inhibira fibrilaciju alfa-sinukleina.[61] Za ove poremećaje, također je podrazumijevajući i Epstein-Barrov virus.[62]
U rijetkim slučajevima porodičnih oblika Parkinsonove bolesti, postoji genska mutacija kodiranja alfa-sinukleina. Do sada je identifikovano pet tačkastih mutacija: A53T,[63] A30P,[64] E46K,[65] H50Q[66] i G51D;[67] međutim, u genu SNCA, s parkinsonizmom povezano je ukupno 19 mutacija: A18T, A29S, A53E, A53V, E57A, V15A, T72M, L8I, V15D, M127I, P117S, M5T, G93A, A E83G.[68]
Prijavljeno je da neke mutacije utiču na inicijaciju i korake amplifikacije procesa agregacije.[69][70] Genomske duplikacije i umnožavanje gena izgledaju kao rijedak uzrok Parkinsonove bolesti u drugim lozama, iako je češći od tačkastih mutacija.[71][72] Stoga određene mutacije alfa-sinukleina mogu uzrokovati stvaranje fibrila sličnih amiloidima koji doprinose Parkinsonovoj bolesti. Prekomjerna ekspresija alfa-sinukleina divljeg tipa ili A53T-mutantnog alfa-sinukleina kod primata dovodi do taloženja alfa-sinukleina u ventralnom dijelu srednjeg mozga, degeneracije dopaminskog sistema i narušenih motorinih performansi.[73]
Određeni dijelovi proteina alfa-sinukleina mogu imati ulogu u tauopatijama.[74][75][76]
Prion skioblik proteina alfa-sinukleina može biti uzročnik bolesti atrofija više sistema.[77][78][79]
Opisani su samoreplicirajući amiloidni sklopovi alfa-sinukleina koji su nevidljivi za amiloidnu boju tioflavin-T i koji se mogu akutno širiti u neuronima i in vitro i in vivo.[81]
Antitijela protiv alfa-sinukleina zamenila su antitijela protiv ubikvitina, kao zlatnog standarda za imunobojenje Lewyjevih tela.[82] Centralni panel na slici desno pokazuje glavni put za agregaciju proteina. Monomerni α-sinuklein se prirodno odvija u rastvoru, ali se također može vezati za membrane u α-heliksnom obliku. Čini se vjerojatnim da ova dva tipa postoje u ravnoteži unutar ćelije, iako to nije dokazano. Iz rada in vitro, jasno je da se nesavijeni monomer može prvo agregirati u male oligomerne tipove koji se mogu stabilizirati interakcijama sličnim β-listu, a zatim u nerastvorljive fibrile veće molekulske težine. U ćelijskom kontekstu, postoje neki dokazi da prisustvo lipida može podstaknuti stvaranje oligomera: α-sinuklein također može formirati prstenaste strukture nalik porama koje su u interakciji s membranama. Taloženje α-sinukleina u patološke strukture kao što su Lewyjeva tijela vjerovatno je kasni događaj koji se javlja u nekim neuronima. Na lijevoj strani su neki od poznatih modifikatora ovog procesa. Električna aktivnost u neuronima mijenja povezanost α-sinukleina sa vezikulama i može također stimulirati polo-like kinaze 2 (PLK2), za koje se pokazalo da fosforiliraju α-sinuklein na Ser129. Predloženo je da budu uključene i druge kinaze. Kao i fosforilacija, skraćivanje putem proteaza kao što su kalpaini i nitracija, vjerovatno putem dušik-oksida (NO) ili drugih reaktivnih azotnih vrsta koje su prisutne tokom upale, što modificira sinuklein tako da ima veću sklonost agregaciji . Dodavanje ubikvitina (prikazano kao crna tačka) Lewyjevim tijelima je vjerovatno sekundarni proces taloženja. Na desnoj strani su neki od predloženih ćelijskih ciljeva za toksičnost posredovanu α-sinukleinom, koji uključuju (od vrha do dna) ER-Golgijev transport, sinapsne vezikule, mitohondrije i lizosome i druge proteolitske mhanizme. U svakom od ovih slučajeva, predlaže se da α-sinuklein ima štetne efekte, koji su navedeni ispod svake strelice, iako još nije jasno da li je bilo šta od njih neophodno ili dovoljno za toksičnost u neuronima.
Interakcije protein-protein
[uredi | uredi izvor]Pokazalo se da alfa-sinuklein reaguje sa
- Dopaminskim receptorom,[83][84]
- Parkin (ligaza),ma[85][86]
- Fosfolipaza D1,[87]
- SNCAIP,[88][89][90][91]
- Tau-proteinom.[92][93][94]
- Beta amiloidom[95]
Također pogledajte
[uredi | uredi izvor]Reference
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Vanjski linkovi
[uredi | uredi izvor]- alpha-Synuclein na US National Library of Medicine Medical Subject Headings (MeSH)
- Lokacija ljudskog genoma SNCA i stranica sa detaljima o genu SNCA u UCSC Genome Browseru.