2012年9月13日 電 /生物谷BIOON/ --近日,，來自紐卡斯爾大學的研究者揭示了大腦神經(jīng)元,、神經(jīng)細胞以及大腦其它部分變老的分子機制,。相關成果刊登在了雜志Aging Cell上，該項研究為理解神經(jīng)元如何衰老提供了一些思路,，這或許為治療如阿爾茲海默癥等疾病帶來一定幫助,。
老化過程是我們機體細胞和分子固有的一種現(xiàn)象，以前有研究者識別出了一種分子途徑可以和對細胞損傷產(chǎn)生反應,，而且可以使得細胞進行分裂,，俗稱為細胞老化現(xiàn)象。然而有些細胞并不具有繼續(xù)分裂的能力,，就比如大腦中的神經(jīng)元,。如今，由教授Thomas von Zglinicki領導的這項研究揭示了大腦中的神經(jīng)元同樣也可以遵循細胞衰老的過程,。
通過對特殊的年老老鼠進行研究,，研究者發(fā)現(xiàn)了神經(jīng)元的老化的確遵循了成纖維細胞開始衰老的規(guī)則，成纖維細胞可以在皮膚中進行分裂進而修復傷口,。
DNA損傷的反應可以重新變成開始衰老的成纖維細胞,，進而產(chǎn)生并且分泌出一種對宿主危險的物質，包括無氧自由基或者活性氧,，并且可以促使信號分子的促炎癥反應,。這將使得衰老細胞不蹲損傷，最終被臨近的正常細胞所替代,。
如今,，這項研究解釋了神經(jīng)元的衰老遵循著成纖維細胞衰老的規(guī)則。研究者von Zglinicki說,，“我們需要發(fā)現(xiàn),，我們在小鼠大腦中檢測到的機制是否人類的大腦衰老和認知力降低一樣，這或許為理解大腦衰老的過程提供一定的思路,。”（生物谷Bioon.com）
編譯自：Discovering how the brain ages
doi:10.1111/j.1474-9726.2012.00870.x
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Postmitotic neurons develop a p21-dependent senescence-like phenotype driven by a DNA damage response
Diana Jurk1,†, Chunfang Wang2,†, Satomi Miwa1,†, Mandy Maddick1, Viktor Korolchuk1, Avgi Tsolou3, Efstathios S. Gonos3, Christopher Thrasivoulou4, M. Jill Saffrey2, Kerry Cameron1, Thomas von Zglinicki1
In senescent cells, a DNA damage response drives not only irreversible loss of replicative capacity but also production and secretion of reactive oxygen species (ROS) and bioactive peptides including pro-inflammatory cytokines. This makes senescent cells a potential cause of tissue functional decline in aging. To our knowledge, we show here for the first time evidence suggesting that DNA damage induces a senescence-like state in mature postmitotic neurons in vivo. About 40–80% of Purkinje neurons and 20–40% of cortical, hippocampal and peripheral neurons in the myenteric plexus from old C57Bl/6 mice showed severe DNA damage, activated p38MAPkinase, high ROS production and oxidative damage, interleukin IL-6 production, heterochromatinization and senescence-associated β-galactosidase activity. Frequencies of these senescence-like neurons increased with age. Short-term caloric restriction tended to decrease frequencies of positive cells. The phenotype was aggravated in brains of late-generation TERC−/− mice with dysfunctional telomeres. It was fully rescued by loss of p21(CDKN1A) function in late-generation TERC−/−CDKN1A−/− mice, indicating p21 as the necessary signal transducer between DNA damage response and senescence-like phenotype in neurons, as in senescing fibroblasts and other proliferation-competent cells. We conclude that a senescence-like phenotype is possibly not restricted to proliferation-competent cells. Rather, dysfunctional telomeres and/or accumulated DNA damage can induce a DNA damage response leading to a phenotype in postmitotic neurons that resembles cell senescence in multiple features. Senescence-like neurons might be a source of oxidative and inflammatory stress and a contributor to brain aging.
