Shuɗin methylene da progeria: darussa daga samfurin tsufar ƙwayoyin halitta

Sauyin harafi guda a wani gene yana sa yara tsufa cikin sauri mai ban tsoro. Zubewar gashi, taurin gaɓoɓi, ƙuntacewar jijiyoyin jini, da tsawon rayuwar da ake tsammani wanda bai wuce shekarun samartaka ba. Wannan cutar ita ce Hutchinson-Gilford progeria syndrome, kuma tsawon shekaru bincikenta ya mayar da hankali kan cibiyar ƙwayar halitta, inda furotin ɗin da ya samu sauyi yake yin lahani. Wani bincike na 2016 daga Jami'ar Maryland ya tambayi wata tambaya dabam: yaya mitochondria suke a waɗannan ƙwayoyin halitta? Amsar ta haɗa sassa biyu na ƙwayar halitta, kuma wani rini shuɗi mai shekara ɗari ya shafi dukansu.

Binciken na Xiong da abokan aikinsa ne, wanda aka wallafa a Aging Cell a 2016. An gudanar da shi gaba ɗaya da ƙwayoyin halitta da aka raina a dakin gwaje-gwaje. Wannan gaskiyar ce tushen fahimtar duk abin da ke ƙasa. Sakamakon binciken na gaske ne kuma takamaimai. Haka ma iyakar abin da zai iya faɗa game da wani magani takamaimai ce.

Samfurin: sauyin gado guda, furotin guda mai manne wa

Progeria tana farawa da maye gurbin C da T a matsayi na 1824 na gene ɗin LMNA. Sauyin ba ya canza wani amino acid. Yana kunna wani ɓoyayyen wurin haɗa sassan RNA, wanda ke cire amino acids 50 daga furotin lamin A. Wannan gajeriyar sigar, da ake kira progerin, tana rasa wurin yankewa wanda a al'ada zai ba ƙwayar halitta damar cire abin da ke ɗaure ta na farnesyl. Saboda haka, progerin yana ci gaba da riƙe farnesyl har abada kuma yana manne wa fatar cikin cibiyar ƙwayar halitta, inda lamin A na al'ada yake mannewa yana kuma sakewa lokaci-lokaci.

An rubuta sakamakon da hakan ke haifarwa a cibiyar ƙwayar halitta sosai, kuma ana iya ganinsa da madubin ƙara girma. Cibiyoyin suna fitar da kumbura kuma suna yin lanƙwashe maimakon su riƙe siffar ƙwai mai santsi. Heterochromatin, wato DNA mai matuƙar cunkushewa wanda ba ya aiki kuma a al'ada yake shimfiɗe a gefen cibiyar, yana raguwa. Ayyukan dubban genes suna canzawa. Ka ɗauki lamina ta cibiyar ƙwayar halitta a matsayin tsarin tallafi a bayan takardar bangon ɗaki: idan aka walda wani ɓangaren tallafin a wurin da bai dace ba, bangon yana kumbura kuma tsarin zane a takardar yana karkacewa a duk ɗakin.

Binciken ya yi amfani da fibroblasts na fata daga marasa lafiya masu progeria tare da ƙwayoyin kwatance da aka yi wa adadin zagayen canja wurin raino iri ɗaya. Haka kuma ya yi amfani da wani rukuni na biyu da aka sauya domin fibroblasts na al'ada su samar da progerin kai tsaye. Ƙwayoyin da aka sauya sun sami lahani iri ɗaya, wanda ya nuna cewa progerin ne sanadin, ba tarihin marasa lafiyar ko tsawon lokacin rainon ƙwayoyin ba. Tsananin lahani ya bi adadin progerin: rukunin da ya samar da progerin fiye da sauran ya nuna lahani mafi tsanani a dukkan ma'aunan.

Yadda mitochondria suka kasance

Mitochondria na fibroblasts masu lafiya suna samar da wata hanyar sadarwa mai rassa a kewaye da cibiyar ƙwayar halitta, wato dogayen ƙananan bututu da suke tafiya kan hanyoyin tsarin tallafin cikin ƙwayar. A rukunonin progeria, wannan hanyar sadarwar ta ɓace. Mafi yawan mitochondria sun rarrabu zuwa ƙananan sassa, da yawa sun kumbura, kuma hotunan madubin lantarki sun nuna cewa adadin sassan cikin ƙwayoyin da suka lalace sosai ya ƙaru zuwa kusan ninki biyu. Hotunan da aka ɗauka a jere cikin lokaci sun nuna cewa suna tafiya gajerun nisan zango cikin saurin da bai kai na ƙwayoyin kwatance ba.

Aiki ya bi yanayin siffa. Superoxide na mitochondria da matakan sinadaran da ke haddasa oxidation a duk ƙwayar halitta sun ƙaru. Ƙarin ƙwayoyin halitta sun nuna tangarɗa a bambancin ƙarfin lantarki a fatar mitochondria. Samar da ATP ya ragu. Babu ɗaya daga cikin waɗannan da yake abin mamaki idan aka dube shi shi kaɗai, domin mitochondria da suka lalace suna zubar da nau'o'in oxygen masu saurin yin martanin sinadarai kuma suna samar da ƙarancin makamashi. Sabon abin shi ne sanadin da aka gabatar. PGC-1alpha, wani mai taimakawa kunna kwafin bayanan genes wanda yake jagorantar samar da mitochondria ta hanyar wasu masu sarrafawa da ke ƙarƙashinsa kamar NRF1, TFAM, da masu sarrafa haɗuwa da rabuwar mitochondria MFN1, MFN2, OPA1, FIS1, da DRP1, ya ragu zuwa kusan ɗaya bisa takwas a matakin mRNA a ƙwayoyin progeria, tare da raguwar furotin da ta yi daidai da hakan. Da alama progerin yana danne babban maɓallin samarwa da kula da mitochondria. Wannan alaƙar tsakanin lalacewar lamina ta cibiyar ƙwayar halitta da sarrafa makamashi wani ɓangare ne na bayani mafi faɗi game da samar da makamashi a mitochondria, kuma an tattauna ɓangaren sinadaran oxidation na wannan daidaito a bayanin damuwar oxidation da sarrafa ROS.

Abin da shuɗin methylene ya canza

Masu binciken sun yi amfani da shuɗin methylene mai taro na 100 nanomolar, wanda taro ne mai ƙanƙanta, a ƙwayoyin halittar ba tare da katsewa ba na tsawon makonni. A tsarin rainon ƙwayoyin halitta, wannan doguwar hulɗa ce mai sauƙi, ba ɗan taɓawar magani na gajeren lokaci ba. Shuɗin methylene yana sauyawa tsakanin sigar da ta fuskanci oxidation da sigar da ta fuskanci reduction, kuma yana iya ɗaukar electrons a cikin mitochondria. Wannan ne dalilin da ya sa ake bayyana shi a matsayin sinadarin redox mai nufar mitochondria, maimakon antioxidant na yau da kullum wanda ake cinye shi yayin da yake kawar da wani sinadarin oxidation guda.

Mitochondria sun amsa a ƙwayoyin al'ada da na progeria. ATP ya ƙaru, matakan sinadaran oxidation sun ragu, kuma rabon mitochondria masu lahani mai tsanani ya ragu. Samar da PGC-1alpha ya farfaɗo wani ɓangare, tare da wasu abubuwan da yake sarrafawa. Har zuwa nan, wannan tasiri ne na tallafa wa mitochondria gaba ɗaya, ba wanda ya keɓanta da progeria ba.

Sakamakon cibiyar ƙwayar halitta ne ya ba da mamaki, kuma ya keɓanta da ƙwayoyin da ke da cutar. Nazarin siffa ta hanyar auna ƙididdiga ya nuna raguwar kumburar cibiyar. Jimillar lamins A da C ta ƙaru. Abin da ya fi ɗaukar hankali shi ne sauyin wuraren da progerin yake: a ƙwayoyin progeria da ba a yi musu amfani da sinadarin ba, kusan 30 cikin ɗari kawai na progerin suke a ɓangaren nucleoplasm mai iya narkewa, yayin da sauran suke manne da fatar cibiyar. Bayan amfani da sinadarin, rabon mai iya narkewa ya ƙaru zuwa kusan 65 cikin ɗari, kusa da halayyar lamin na al'ada. Idan progerin ya rabu da fatar cibiyar, yana jan ƙarancin maƙwabtansa tare da shi, kuma ɓangarorin lamins A da C masu iya narkewa sun farfaɗo su ma.

Sakamakon wannan sakin, siffofi biyu na cibiyar ƙwayar halitta sun inganta. Heterochromatin da ke kewaye da cibiyar, wanda aka bincika da madubin lantarki da kuma yin rini domin gano furotin heterochromatin HP1-alpha, ya farfaɗo ta yadda ake iya gani. Kuma karanta jerin RNA ya nuna cewa jimillar RNA da ƙwayar ke samarwa tana komawa kusa da yanayin al'ada: ƙwayoyin progeria da ba a yi musu amfani da sinadarin ba sun bambanta da ƙwayoyin kwatance a fiye da genes 3,200, yayin da waɗanda aka yi musu amfani da shi suka bambanta a kusan 1,670. A ƙwayoyin al'ada, amfani da sinadarin iri ɗaya ya canza genes 'yan dozin kaɗan kawai. Wannan yana nuna cewa tasirin a cibiyar yana da alaƙa da progerin, maimakon ya zama wata girgizar aikin kwafin bayanan genes gaba ɗaya. An bayyana ƙa'idar cewa gwaje-gwajen ƙwayoyin halitta da dabbobi suna amsa tambayoyi masu iyaka fiye da yadda kanun labaransu ke nunawa a yadda ake karanta binciken shuɗin methylene.

Dalilin da ya sa wannan ba magani ba ne

Iyakoki huɗu suna riƙe wannan bincike a inda ya dace: cikin dakin gwaje-gwaje.

Na farko, komai ya faru a kwanonin gwaji. Fibroblasts da aka raina ba su da wadatar jini, yanayin tsarin garkuwar jiki, tsarin nama, da yadda magani ke aiki a duk jiki, waɗanda suke tantance ko wani sinadari zai kai wurin da ake nufi ko a'a. Ba a ba wata dabba sinadarin ba, kuma ba a yi wa wani mara lafiya magani ba a wannan binciken.

Na biyu, fibroblasts na progeria samfurin nau'in ƙwayar halitta guda ne. Cutar tana haddasa mutuwa musamman ta hanyar tasirinta a jijiyoyin jini, ƙashi, da kitse, kuma binciken ya duba fibroblasts ne kawai tare da samfurin tsoka mai santsi guda. Sauran nau'o'in nama na iya nuna hali dabam.

Na uku, gyaran cibiyar ƙwayar halitta ya samo asali ne daga hulɗa mai ci gaba na tsawon makonni da taron sinadarin na nanomolar a ruwan rainon ƙwayoyi. Taron sinadari a kwanon gwaji ba adadin maganin da za a ba mutum ba ne, kuma babu abin da ke cikin takardar binciken da ya sauya 100 nanomolar a ruwan raino zuwa tsarin ba mutum magani. Shuɗin methylene yana da nasa alaƙar adadi da amsa, da nasa yanayin aminci a sauran fannonin likitanci, kuma wannan binciken bai ba da wata hujjar amfani da shi a gida ba. Bayanin aminci na gaba ɗaya yana cikin amincin shuɗin methylene da illolinsa.

Na huɗu, progeria ba tsufar al'ada ba ce. Cuta ce mai wuya da sauyin gado guda yake haddasawa, wadda tsarin tallafin cibiyar ƙwayar halitta yake lalacewa ta wata hanya takamaimai. Sinadarin da yake rage wannan takamaiman lalacewa a ƙwayoyin da aka raina ba ya ba da bayani mai yawa game da tsufa a mutanen da ba su da wannan sauyin gado. Halayen ƙwayoyin suna ba da damar fahimtar sadarwa tsakanin cibiyar ƙwayar halitta da mitochondria, ba sakamakon ƙara tsawon rayuwa ba ne.

Saboda haka, taƙaitaccen bayanin da ya dace yana da sharudda. A fibroblasts na progeria, progerin yana danne PGC-1alpha kuma yana barin mitochondria a rarrabe, masu jinkirin motsi, cike da sinadaran oxidation, kuma masu ƙarancin makamashi. Shuɗin methylene mai ƙanƙantar taro ya dawo da ma'aunan aikin mitochondria a duk ƙwayoyin, sannan kuma ya saki progerin daga fatar cibiyar a ƙwayoyin da ke da cutar, tare da farfaɗowar wani ɓangare na siffar cibiyar, heterochromatin, da aikin genes. Wannan aiki a sassa biyu ya sa binciken ya cancanci a san da shi. Bai sa shuɗin methylene ya zama maganin progeria ko tsufa ba.