Ubururu bwa metilene na ALS: impamvu ibisubizo bitandukana mu byitegererezo by'igerageza

Iyo ushakishije ubururu bwa metilene na ALS, ubona ibyemezo bibiri bisa n'ibivuguruzanya. Kimwe kivuga ko iryo bara ry'ubururu ryarinze uturemangingo tw'imyakura mu byitegererezo bya ALS. Ikindi kikavuga ko nta cyo ryakoze mu mbeba y'icyitegererezo cya ALS. Byombi bishingira ku nyandiko z'ubushakashatsi nyazo, kandi izo nyandiko zombi zikwiye kwitabwaho. Uko kuvuguruzanya gushira iyo ugaragaje igitekerezo kiri inyuma ya buri gerageza: icyitegererezo ni cyo kigena icyo ushobora kwemeza.

Igisubizo kibonetse mu nyo ni icyo ushobora kwemeza ku nyo. Igisubizo kibonetse mu ifi ikiri urwana ni icyo ushobora kwemeza ku ifi ikiri urwana. Nta na kimwe gishobora kwemeza ibireba umurwayi keretse uko indwara igenda mu nyamabere bibishyigikiye. Iyi ngingo igereranya inyandiko ebyiri zikunze kuvugwa cyane kugira ngo ubone impamvu ibisubizo byazo bitandukanye.

Amagerageza yombi mu mbonerahamwe imwe

Komeza kureba iyi mbonerahamwe uko usoma. Itandukaniro ryose ry'ingenzi hagati y'ubu bushakashatsi ririmo.

Ingirabuzima fatizo ziratandukanye, amoko y'ibinyabuzima aratandukanye, inzira umuti unyuramo iratandukanye, igihe watangiwe kiratandukanye, n'ibipimo by'ibisubizo biratandukanye. Imiterere y'ingirabuzima fatizo ni rimwe gusa muri ayo matandukaniro atanu, bityo ubu bushakashatsi bwombi ntibushobora kwemeza ko ubururu bwa metilene bukora gusa ku nzira imwe y'imikorere ya ALS. Bwemeza ikintu gifunganye kurushaho ariko gifite akamaro: kugarura imikorere ku rugero rukomeye igihe ibinyabuzima byo mu byitegererezo byoroheje byahuraga n'umuti hakiri kare kandi mu buryo butaziguye ntibyagaragaye mu gihe cyose cy'indwara yo mu nyamabere yahawe umuti mu kanwa igihe kirekire.

Igisubizo cyiza: ibyo ubushakashatsi ku nyo n'amafi bwagaragaje

Ubushakashatsi bwo mu 2012 ku nyo n'amafi bwatumye uturemangingo tw'imyakura tuyobora ingendo mu nyo dukora TDP-43 cyangwa FUS y'umuntu yahindutse, kandi bwateye mRNA y'umuntu yahindutse mu nsoro z'amafi. Ibi ni ibyitegererezo by'uburozi buterwa na poroteyine. Byigana ingaruka z'uburozi bwa poroteyine yahindutse ku ngendo no ku miterere y'uturemangingo tw'imyakura mu gihe cy'iminsi, aho kwigana uko ALS y'umuntu mukuru igenda yose mu gihe cy'imyaka.

Gutanga umuti byatangiye hakiri kare cyane. Inyo zakuriye kuri agari irimo ubururu bwa metilene kuva zisohotse mu magi. Insoro z'amafi zamaze ijoro ryose mu mazi arimo umuti, guhera ku masaha 24 nyuma yo gusama, imyitwarire yazo isuzumwa nyuma y'iminsi igera kuri ibiri. Nta nzitizi hagati y'amaraso n'ubwonko yatandukanyaga umuti n'uturemangingo tw'imyakura nk'uko bigenda mu nyamabere, kandi nta gipimo cy'umuti mu gice cy'amazi cy'amaraso cyangwa mu bwonko cyapimwe.

Muri ibyo bihe, ingaruka zari nini kandi zihamye. 6 na 60 μM byombi byagabanyije kugagara kwiyongera uko inyo za TDP-43 na FUS zisaza. Ku munsi wa 12 w'ubukure, hafi 80 ku ijana by'inyo za TDP-43 zitahawe umuti zari zagagaye, ugereranyije na hafi 10 ku ijana by'inyo zahawe umuti kuva zisohotse mu magi. Isuzuma ry'amasinapusi na ryo ryagaragaje icyerekezo kimwe: inyo za TDP-43 zari zifite ubukangurwe bukabije kuri aldicarb, umuti ukoreshwa mu gusuzuma ihererekanywa ry'ubutumwa hagati y'imyakura n'imikaya, kandi ubururu bwa metilene bwagaruye uko zisubiza hafi y'ibisanzwe. Umubare w'amashami y'uturemangingo tw'imyakura tuyobora ingendo yangirikaga waragabanutse, ingaruka zigaragara cyane kuri 60 μM. Mu mafi, koga guterwa no gukorwaho kwateye imbere cyane, kandi amasokozo y'uturemangingo tw'imyakura tuyobora ingendo yari yaragabanyutse yongeye gukura yegera uburebure busanzwe kuri 30 cyangwa 60 μM, nubwo kugarura imikorere kwabaye igice gusa aho kuba kuzuye.

Amakuru yerekeye ihungabana riterwa na okisidasiyo ahuye n'igisobanuro gishingiye ku kurwanya okisidasiyo. Inyo n'amafi byari bifite impinduka mu ngirabuzima fatizo byagaragaje ibipimo byiyongereye by'amoko ya ogisijeni yitabira cyane mu mikoranire ya shimi, maze biragabanuka nyuma yo guhabwa umuti. Inyo zisanzwe zahawe ubururu bwa metilene na zo zabayeho igihe kirekire cyane kurusha izitahawe umuti igihe zari zashyizwe mu bihe bitera okisidasiyo. Ariko hari imipaka ibiri y'ingenzi. Ingano zose za poroteyine za TDP-43 na FUS zahindutse ntizagabanutse, kandi ubushakashatsi ntibwapimye mu buryo butaziguye ingano z'ibirundo bya poroteyine. Bityo bugaragaza kugarura imikorere butemeje ko ibyo birundo byavanyweho. Umuntu wese ukurikirana uko ibitekerezo ku mikoranire ya redox no kuri mitokondiriya bisanzwe bisobanurwa akwiye gufata iyo mikorere nk'ishyigikiwe n'ibimenyetso, ariko itaremezwa burundu.

Igihe umuti watangiwe ni cyo cyigishije byinshi kurusha ibindi. Iyo abanditsi bategerezaga umunsi wa 5 w'ubukure kugira ngo batangire gutanga umuti, igipimo cyo kugagara ku munsi wa 12 cyabaga hafi 55 ku ijana aho kuba hafi 10 ku ijana iyo umuti watangwaga kuva inyo zisohotse mu magi. Umuti umwe, inyo imwe, impinduka imwe mu ngirabuzima fatizo, ariko ingaruka nto cyane. Guhabwa umuti hakiri kare mu rwego rwo gukumira ni byo byasobanuraga igice kinini cy'inyungu zagaragaraga.

Igisubizo kitagaragaje inyungu: ibyo ubushakashatsi ku mbeba za SOD1 bwagaragaje

Ubushakashatsi bwo mu 2011 ku mbeba bwabajije ikibazo gikomeye kurushaho mu buryo bw'igerageza bufite amabwiriza akomeye. Imbeba za SOD1 G93A zifite inkomoko imwe y'ingirabuzima fatizo zitangira gutitira amaguru y'inyuma, zigakurikirizaho kugenda nabi no gutakaza ubushobozi bwo kwisubiza mu mwanya zisanzwe zihagararamo, zikagera ku cyiciro cya nyuma cyagenwe mbere. Gutanga umuti byatangiye ku munsi wa 45 mbere y'ibimenyetso, bikomeza buri munsi, abagenzuzi bapima ibimenyetso byo mu myakura ku gipimo cya 0 kugeza kuri 6. Iri ni igerageza rikurikirana indwara mu gihe cyayo cyose, bityo rikaba ryegereye ibyo umurwayi yakwitaho kurusha igishushanyo icyo ari cyo cyose cyerekana kugagara mu nyo.

Ibisubizo by'ingenzi ntibyagaragaje inyungu. Muri rusange, indwara yatangiye ku minsi 121 mu mbeba zo kugereranyaho, ugereranyije n'iminsi 124 mu zahawe ubururu bwa metilene; iryo tandukaniro ntiryari rifite akamaro mu ibarurishamibare. Igihe cyo kubaho kugeza ku cyiciro cya nyuma cyari iminsi 167 ugereranyije n'iminsi 170, na byo bidafite akamaro mu ibarurishamibare. Isesengura rito ry'ibisubizo by'inyongera ryagaragaje ibishyigikira umuti: mu ngore, itangira ry'indwara ryatinzeho hafi iminsi 7, kandi inyamaswa zahawe umuti zamaze igihe kirekireho gato mu byiciro byoroheje n'igihe gito mu bikomeye. Kubera ko amatsinda yagabanyijwe hakurikijwe igitsina yari mato kandi hakagereranywa ibyiciro byinshi, ibyo bisubizo bikwiye gufatwa nk'ibitanga ibitekerezo byo kugerageza, aho kuba ibimenyetso byemeza. Nta mubare w'uturemangingo tw'imyakura wapimwe, nta suzuma ry'ibirundo bya SOD1 ryakozwe, kandi nta bimenyetso bya okisidasiyo cyangwa by'ububyimbirwe byapimwe. Bityo ubushakashatsi ntibushobora no kuvuga niba umuti warageze ku byo ugomba gukoreraho ntugire icyo ukora, cyangwa niba utarigeze ukorana na byo kuri iyo ngano. Ingano imwe gusa y'umuti ni yo yageragejwe.

Abanditsi ubwabo bagaragaje imbogamizi ikomeye kurusha izindi, ireba ibisubizo byiza n'ibitagize inyungu. Icyitegererezo cya SOD1 G93A gifite kopi nyinshi kigana neza indwara iterwa n'uburozi bwa SOD1, ariko indwara ya SOD1 ni igice gito cya ALS ihererekanywa mu muryango kandi imikorere yayo y'ibinyabuzima itandukanye n'iy'ubwoko bwinshi bwa ALS butagaragaza ihererekanywa mu muryango. Basabye ko ibishobora kuvamo imiti byongera kugeragezwa mu byitegererezo by'inyamabere bishingiye kuri TDP-43. Icyo gitekerezo cyaje kurushaho kugorana, kuko abanditsi b'ubushakashatsi ku nyo n'amafi bavuga ko ubundi bushakashatsi ku bururu bwa metilene mu mbeba za TDP-43 na bwo butateje imbere ibipimo by'imikorere y'ingendo. Bityo ikinyabutabire gishobora kugaragara nk'igifite ingaruka zikomeye mu cyitegererezo kimwe cya TDP-43, ariko ntikigaragaze inyungu mu kindi cyitegererezo cya TDP-43. Uburyo bw'icyitegererezo bufite akamaro kangana n'ak'ingirabuzima fatizo.

Impamvu gutera imbere mu nyo cyangwa mu ifi bidashobora kwemeza inyungu ku barwayi

Fata buri cyitegererezo nk'igisubiza ikibazo gitandukanye.

Icya mbere, imikorere y'ibinyabuzima iratandukanye. TDP-43 na FUS ni poroteyine zifata kuri aside nikileyike kandi zigira imikoranire ihuriweho y'ingirabuzima fatizo muri ibi byitegererezo byoroheje, mu gihe uburozi bwa SOD1 bukora binyuze ku buryo bw'ibanze butandukanye mu bice bimwe. Umuti woroshya ihungabana rimwe riterwa n'uburozi bwa poroteyine si ngombwa ko woroshya n'irindi. Kandi gutsinda ingaruka zo gukora poroteyine nyinshi birenze ibisanzwe mu nsoro si ngombwa ko bihanura gutsinda kwangirika buhoro kw'imyakura mu bakuru, kujyana n'ububyimbirwe, uruhare rw'uturemangingo twa glia no gucika intege k'umubiri wose.

Icya kabiri, guhura n'umuti biratandukanye. Guhora mu mazi arimo umuti ku gipimo cya mikoromolari si kimwe no kuwufata mu kanwa. Kwinjizwa k'umuti n'amara, guhindurwa kwawo mu mubiri bwa mbere mbere yo kugera mu maraso azenguruka hose, gufata kuri poroteyine zo mu maraso, kwinjira mu bwonko no kuvanwa mu mubiri, byose biri hagati y'umuti wamizwe n'uturemangingo tw'imyakura tuyobora ingendo two mu ruti rw'umugongo. Nta bushakashatsi na bumwe muri bwombi bwapimye ingano z'umuti mu rwungano rw'imyakura, bityo nta na bumwe bushobora guhuza igipimo cyabwo n'icy'ubundi.

Icya gatatu, igihe umuti watangiwe kiratandukanye. Inyungu mu nyo n'amafi zashingiraga cyane ku gutanga umuti mbere y'uko kwangirika kw'indwara kwiyongera. Gutanga umuti mu mbeba na byo byatangiye mbere y'ibimenyetso, ibyo bikaba ari imbaraga z'ubwo bushakashatsi. Nyamara ku bantu, kuvurwa byatangira hafi buri gihe nyuma y'uko ibimenyetso bitangiye, bikaba ari na nyuma kurushaho. Ikimenyetso cy'inyungu zo gukumira mu isuzuma ry'urusoro rimara iminsi ibiri ni intangiriro y'ubushakashatsi, si icyitegererezo cy'ikoreshwa mu buvuzi.

Icya kane, ibipimo by'ibisubizo biratandukanye. Kugagara ku minsi 12, ubukangurwe kuri aldicarb, uburebure bw'amasokozo y'uturemangingo tw'imyakura muri mikorometro n'intera yogwa ni ibiranga imikorere byegereye uburyo umuti ukora. Itangira ry'indwara n'igihe cyo kubaho mu nyamabere bikubiyemo inzira zose zo mu mubiri zisimbura imikorere yangiritse cyangwa zituma ibintu birushaho kugorana. Imiti ikunze guhindura ibyo bipimo byegereye imikorere yayo itahinduye igihe cyo kubaho, ari na yo mpamvu hakoreshwa ibipimo by'igihe kugeza habaye ikintu runaka mu nyamabere.

Abasomyi bashaka urutonde rw'ibyo kugenzura ku nkuru y'ubushakashatsi izakurikiraho bashobora kurukura mu ngingo ivuga uko wasoma ubushakashatsi bubanziriza amagerageza ku bantu: baza ubwoko bw'ikinyabuzima, ingirabuzima fatizo yinjijwemo, ingano y'umuti n'inzira watanzwemo, niba ingano z'umuti mu mubiri zarapimwe, igihe kuvura byatangiriye ugereranyije n'igihe kwangirika kw'indwara kwabereye, niba igipimo cy'igisubizo cyari ikiranga imikorere cy'igihe gito cyangwa uko indwara igenda, n'iba izo ngaruka zarongeye kuboneka muri laboratwari ya kabiri. Ibimenyetso rusange by'ubushakashatsi ku bururu bwa metilene mu bantu ni byo bikomeza kuba aho kugenzura niba hari kimwe muri ibi bimenyetso by'ibanze cyarakomeje kugeza kibaye amakuru y'ubushakashatsi ku barwayi.

Icyo ibi bisobanura ku barwayi n'imiryango yabo

Nta gahunda yemewe yo gukoresha ubururu bwa metilene kuri ALS ikomoka muri izi nyandiko. Ubushakashatsi bwagaragaje inyungu bushyigikira gukomeza ubushakashatsi ku buryo bwa okisidasiyo n'ubw'amasinapusi mu mikorere ya TDP-43 na FUS. Ubushakashatsi butagaragaje inyungu bugabanya ishingiro ryo kwitega ko gutanga umuti mu kanwa igihe kirekire, ku rugero rwo guhura n'umuti rwageragejwe, byahindura uko indwara y'ubwoko bwa SOD1 igenda. Hamwe, bugaragaza ibisubizo bidahuye mu byitegererezo bitandukanye, si inama yo kuvura.

Umutekano ukwiye gusobanurwa mu bushishozi nk'ubushobozi bwo gutanga inyungu. Ubushakashatsi kuri ALS mu mbeba nta cyo buvuga ku ngano y'umuti yakwakoreshwa ku bantu mu mutekano, kandi ubururu bwa metilene bufite ibyago nyabyo byo kwangirika kw'insoro zitukura ku bafite ibura rya G6PD, n'uburozi bwa serotonine iyo bufatanyijwe n'imiti ikora ku buryo bwa serotonine. Gukeka ibura rya G6PD, kuba umuntu afata imiti yo kuvura agahinda gakabije n'impinduka iyo ari yo yose iteganyijwe mu miti, byose bigomba kuganirwaho n'umuganga. Ni kimwe no gusuzuma amakuru rusange ku mutekano w'ubururu bwa metilene mbere y'uko umuntu agira icyo akora ashingiye ku nkuru z'ubushakashatsi bwo muri laboratwari.

Umwanzuro ushobora kuvugwa mu nteruro imwe. Ubururu bwa metilene bwagaruye cyane ibiranga imikorere mu nyo n'ibyana by'amafi bya TDP-43 na FUS iyo byahuraga n'umuti hakiri kare, ariko mu bushakashatsi bw'imbeba za SOD1 zahawe umuti mu kanwa igihe kirekire, nta nyungu ifatika yabonetse ku gutinza itangira ry'indwara cyangwa ku gihe cyo kubaho; bityo igisobanuro kidahisha ukuri ni uko ibi ari ibimenyetso bishingiye ku cyitegererezo kandi bidashyigikira gukoresha uwo muti ku barwayi.