Te kikorangi metilīni me te progeria: ngā akoranga mai i tētahi tauira koroheketanga pūtau

Nā te panonitanga o tētahi pū kotahi i roto i tētahi ira kotahi ka koroheketia ngā tamariki i te tere whakamataku. Ka ngahoro ngā makawe, ka mārō ngā hononga, ka whāiti ngā ia toto matua, ā, kei ngā tau taiohi te roa o te oranga e matapaetia ana. Ko taua mate ko te mate progeria Hutchinson-Gilford. Mō ngā tau maha, i aro ngā rangahau ki te karihi, te wāhi e mahi kino ai te pūmua kua rerekē nā te irakētanga. I te tau 2016, i uia he pātai kē e tētahi rangahau nō te Whare Wānanga o Maryland: he pēhea te āhua o ngā mitokōria i roto i ēnei pūtau? Nā te whakautu i tūhono ngā wāhanga e rua o te pūtau, ā, i pā tētahi waikano kikorangi kua kotahi rau tau e mōhiotia ana ki aua wāhanga e rua.

Nā Xiong me ōna hoa taua rangahau, i whakaputaina ki Aging Cell i te tau 2016. He pūtau whakatipu anake i whakamahia. Ko taua meka te tūāpapa mō ngā kōrero katoa kei raro iho nei. He tūturu ngā kitenga, ā, he whāiti te whānuitanga. He mārama anō hoki te tawhiti i waenga i aua kitenga me tētahi maimoatanga.

Te tauira: kotahi te irakētanga, kotahi te pūmua piri

Ka tīmata te progeria i te whakakapinga o te C ki te T i te tūnga 1824 o te ira LMNA. Kāore taua panonitanga e whakarerekē i tētahi waikawa amino. Ka whakahohe kē i tētahi wāhi huna mō te tapahi me te tūhono RNA, ā, nā tēnei ka tangohia ngā waikawa amino e 50 i te pūmua lamin A. Ka kīia taua hua kua whakapotoa ko te progerin. Ka ngaro tōna wāhi tapahi e āhei ai te pūtau, i te tikanga noa, ki te tango i tōna punga farnesyl. Nā reira ka noho pūmau te rōpū farnesyl ki te progerin, ka piri tonu hoki te progerin ki te kiriuhi o roto o te karihi, te wāhi e piri ai, e wehe ai te lamin A noa i roto i tōna huringa.

Kua tino tuhia ngā pānga ki te karihi, ā, ka kitea i raro i te karu whakarahi. Ka pupuhi, ka kōmingomingotia ngā karihi, kāore e mau ki te āhua porotītaha māeneene. Ka angiangi haere te heterochromatin, arā, te DNA kikī kāore e kaha ki te whakaputa ira, e takoto noa ana i te tapa o te karihi. Ka rerekē te whakaputanga o ngā ira mano tini. Whakaarohia te lamina o te karihi hei anga tautoko i muri i te pepa pakitara: ki te paiherea tētahi wāhanga o taua anga ki te tūnga hē, ka pupuhi te pakitara, ka kōpiko hoki te tauira o te pepa puta noa i te rūma.

I whakamahia e te rangahau ngā fibroblast kiri nō ngā tūroro progeria, arā, ngā pūtau e hanga ana i ngā kiko tūhonohono. I whakaritea ēnei ki ngā pūtau whakahaere kua whakawhitia ki ngā ipu whakatipu hou he ōrite te maha o ngā wā. I whakamahia anō he rārangi pūtau tuarua i whakarerekētia kia whakaputa tika ai ngā fibroblast noa i te progerin. I puta aua hapa anō ki ngā pūtau i whakarerekētia. Nā tēnei i tautuhi ko te progerin te pūtake, kaua ko te hītori o ngā tūroro, ko te roanga rānei o te wā whakatipu. I hāngai te taumaha o ngā hapa ki te nui o te progerin: he kino ake ngā hapa katoa i te rārangi pūtau i whakaputa nui ake i te progerin.

Te āhua o ngā mitokōria

I ngā fibroblast hauora, ka hanga ngā mitokōria i tētahi whatunga manga huri noa i te karihi, he ngongo roa e haere ana i ngā ara o te anga pūtau. I ngā rārangi pūtau progeria, kua ngaro taua whatunga. He nui ake te ōwehenga o ngā mitokōria kua wāwāhia, he maha kua pupuhi, ā, i kitea mā te karu whakarahi irahiko kua tata ki te rua whakareatanga te maha o ngā whēkauiti kua tino pakaru. I kitea i ngā whakaahua raupapa ā-wā he poto ake ngā tawhiti i haere ai aua mitokōria, he pōturi ake hoki te tere i ērā o ngā pūtau whakahaere.

I whai te mahi i te āhua. I piki ngā taumata o te superoxide i roto i ngā mitokōria me ngā matū whakahāora puta noa i te pūtau. He maha ake ngā pūtau i kitea kua whakararu te pūmanawa hiko o te kiriuhi. I heke te whakaputanga ATP. Ki te tirohia takitahitia ēnei, ehara i te mea ohorere, nā te mea ka turuturu ngā momo hāora tauhohe i ngā mitokōria kua pakaru, ā, ka iti ake te pūngao ka mahia. Ko te mea hou ko te pūtake i whakaarohia. Ko te PGC-1alpha he kaitautoko whakahohe tuhinga ira e akiaki ana i te hanganga o ngā mitokōria mā ngā tauwehe ka mahi i muri iho, pērā i te NRF1, TFAM, me ngā kaiwhakahaere hanumi, wehe hoki, arā, te MFN1, MFN2, OPA1, FIS1, me te DRP1. I ngā pūtau progeria, i heke tōna taumata mRNA ki te tata ki te kotahi hauwaru, ā, i heke rite hoki te pūmua. Ko te āhua nei, e pēhi ana te progerin i te pana matua mō te hanga me te tiaki mitokōria. Ko taua hononga i waenga i te pakarutanga o te lamina karihi me te pākia pūngao tētahi wāhanga o te whakamārama whānui mō te whakaputanga pūngao a ngā mitokōria. Ka kōrerotia te taha whakahāora o taua taurite i ngā kōrero mō te ahotea whakahāora me te whakahaere ROS.

Ngā mea i whakarerekētia e te kikorangi metilīni

I hoatu e ngā kairangahau te kikorangi metilīni ki ngā pūtau i te kukūtanga iti o te 100 nanomolar, mō ngā wiki maha, me te kore e haukotia. I roto i te horopaki whakatipu pūtau, he pānga roa, he pānga ngāwari tēnei, kāore i rite ki tētahi tukunga rongoā poto. Ka huri haere te kikorangi metilīni i waenga i ōna āhua kua whakahāoratia me ōna āhua kua whakahekea, ā, ka taea e ia te kawe irahiko i roto i ngā mitokōria. Nā reira ka whakaahuatia hei pūhui tauhohenga whakahāora-whakaheke e aro ana ki ngā mitokōria, kaua hei matū ārai whakahāora noa ka pau i te wā e whakakore ai i tētahi matū whakahāora kotahi.

I urupare ngā mitokōria i ngā pūtau noa me ngā pūtau progeria. I piki te ATP, i heke ngā taumata matū whakahāora, ā, i iti haere te ōwehenga o ngā mitokōria kua tino hapa. I hoki mai tētahi wāhanga o te whakaputanga PGC-1alpha, me ētahi o ngā mea e whakahaerehia ana e ia i muri iho. Tae noa ki konei, he pānga tautoko whānui tēnei ki ngā mitokōria, kāore i motuhake ki te progeria.

Ko ngā hua mō te karihi te mea ohorere, ā, i motuhake ēnei ki ngā pūtau mate. I kitea mā te tātari ine āhua kua iti haere ngā pupuhitanga o te karihi. I piki te tapeke o ngā lamin A me C. Ko te mea tino kitea ko te nekehanga o te progerin ki ngā wāhi kē: i ngā pūtau progeria kāore i rongoātia, tata ki te 30 ōrau anake o te progerin i noho ki te hautanga wairewa o te wai o roto i te karihi, ā, ko te toenga i mau ki te kiriuhi. Whai muri i te maimoatanga, i piki te wāhanga wairewa ki te tata ki te 65 ōrau, he tata ki te whanonga o te lamin noa. Ina wetekina i te kiriuhi, ka iti ake ngā pūmua tata ka tōia e te progerin, ā, i hoki mai hoki ngā hautanga wairewa o ngā lamin A me C.

Nā taua wetekina, i pai ake ngā āhuatanga karihi e rua i kitea. I āta kitea te hoki mai o te heterochromatin huri noa i te karihi, i tirohia mā te karu whakarahi irahiko me te tae whakarite mō te pūmua heterochromatin HP1-alpha. I kitea hoki mā te whakatau raupapa RNA e neke ana te huinga RNA katoa ki tōna āhua noa: he rerekē ngā pūtau progeria kāore i rongoātia i ngā pūtau whakahaere i ngā ira neke atu i te 3,200, engari he rerekē ngā pūtau progeria i rongoātia i ngā ira tata ki te 1,670. I ngā pūtau noa, he torutoru tekau noa iho ngā ira i whakarerekētia e taua maimoatanga. E tautoko ana tēnei i te whakaaro e herea ana te pānga ki te karihi ki te progerin, kāore i ahu mai i tētahi whakarerekētanga whānui o te tuhinga ira. Ka whakamāramatia i te pānui rangahau mō te kikorangi metilīni te mātāpono he whāiti ake ngā pātai ka taea te whakautu mā ngā tauira pūtau me ngā tauira kararehe i tā ngā upoko kōrero e whakapae ai.

Te take ehara tēnei i te maimoatanga

E whā ngā herenga e pupuri ana i tēnei rangahau ki tōna wāhi tika: ki roto i te taiwhanga.

Tuatahi, i mahia ngā mea katoa i roto i ngā ipu whakatipu. Kāore ngā fibroblast e whakatipuria ana e whai i te rere toto, te horopaki pūnaha ārai mate, te hanganga kiko, me ngā tukanga rongoā o te tinana katoa e whakatau ana mēnā ka tae rawa tētahi pūhui ki tōna whāinga. Kāore tētahi kararehe i hoatu he horopeta, kāore hoki tētahi tūroro i rongoātia i roto i tēnei pepa.

Tuarua, he tauira ngā fibroblast progeria mō tētahi momo pūtau kotahi. Ko te nuinga o ngā matenga i tēnei mate ka ahu mai i ōna pānga ki ngā ia toto matua, ngā kōiwi, me te kiko ngako. I tirohia e te rangahau ngā fibroblast me tētahi tauira uaua māeneene anake. Tērā pea he rerekē te whanonga o ētahi atu kiko.

Tuatoru, i ahu mai te whakaoranga karihi i te pānga nanomolar kāore i haukotia mō ngā wiki maha i roto i te wai whakatipu pūtau. Ehara ngā kukūtanga i roto i te ipu i te horopeta, ā, kāore he mea i roto i te pepa e huri ana i te 100 nanomolar i te wai whakatipu hei hōtaka hoatu rongoā mā te tangata. Kei ētahi atu whakamahinga hauora o te kikorangi metilīni ōna ake pānga e hāngai ana ki te horopeta me ōna ake āhuatanga haumaru. Kāore tēnei rangahau e whakarato tūāpapa mō te whakamahi i te kāinga. Kei te haumaru me ngā pānga taha o te kikorangi metilīni te horopaki haumaru whānui.

Tuawhā, ehara te progeria i te koroheketanga noa. He mate onge tēnei nō tētahi irakētanga kotahi, ā, ka pakaru te anga tautoko o te karihi i tētahi ara motuhake. He iti noa tā tētahi pūhui e whakaiti ana i taua pakarutanga motuhake i ngā pūtau whakatipu e whakaatu ai mō te koroheketanga o te hunga kāore i a rātou taua irakētanga. He matapihi te āhuatanga pūtau ki te whakawhiti kōrero i waenga i te karihi me ngā mitokōria, ehara i te hua mō te whakaroa i te oranga.

Nā reira, me here te whakarāpopototanga tika ki ngā tikanga o te rangahau. I ngā fibroblast progeria, ka pēhi te progerin i te PGC-1alpha, ka waiho ngā mitokōria kia wāwāhia, kia pōturi, kia nui ngā matū whakahāora, kia iti hoki te pūngao. Nā te kikorangi metilīni kukūtanga iti i whakahoki ngā inenga mahi mitokōria i ngā pūtau katoa, ā, i wetekina anō te progerin i te kiriuhi karihi i ngā pūtau mate. I whai mai te hoki mai o tētahi wāhanga o te āhua karihi, te heterochromatin, me te whakaputanga ira. Nā taua mahi ki ngā wāhanga e rua e whai take ai te mōhio ki tēnei rangahau. Kāore tēnei e whakarite i te kikorangi metilīni hei maimoatanga mō te progeria, mō te koroheketanga rānei.