在近日出版的Neuron雜志上,，美國科學(xué)家表示他們正在開發(fā)可選擇性地提高大腦中的基因表達(dá)的新技術(shù)，藉以治療精神疾病及神經(jīng)系統(tǒng)疾病,。許多證據(jù)顯示,，針對該機(jī)制的化合物能提高老鼠的學(xué)習(xí)和記憶能力。
過去的幾年內(nèi),，神經(jīng)學(xué)家已經(jīng)開始認(rèn)識到表觀遺傳學(xué)的重要性,。表觀遺傳指在大腦中，尤其是在記憶中改變基因表達(dá)而不改變DNA的分子過程,，表觀遺傳關(guān)鍵的調(diào)節(jié)器之一是一群名為組蛋白脫乙?；拿福℉DACs），它觸發(fā)DNA將鄰近的蛋白質(zhì)纏繞得更緊,，最終抑制基因表達(dá),。最近的研究已經(jīng)證明，這些酶的抑制藥物能加強(qiáng)正常老鼠和認(rèn)知受到損害的老鼠的學(xué)習(xí)能力,。
美國麻省理工學(xué)院的神經(jīng)科學(xué)家蔡理慧（音譯）團(tuán)隊(duì)去年證明,，給腦部受損的老鼠使用HDAC抑制劑，能夠使老鼠恢復(fù)失去的記憶。
盡管科學(xué)家仍然不能準(zhǔn)確地知道外部的控制如何影響記憶,，但理論認(rèn)為,，鍛煉、視覺強(qiáng)化或者藥物放松了DNA等可觸發(fā)與神經(jīng)可塑性相關(guān)的基因表達(dá),?；虮磉_(dá)的增加能觸發(fā)新的神經(jīng)聯(lián)系，從而鞏固神經(jīng)回路,。美國國立藥物濫用研究所表觀遺傳學(xué)項(xiàng)目主管約翰?斯特里說：“也許我們的大腦正在使用這些外部機(jī)制來讓我們學(xué)習(xí)和記住事情,，或者提供充足的可塑性來允許我們學(xué)習(xí)和調(diào)試。”
蔡理慧表示,，已有充分證據(jù)證明,，HDAC抑制劑能大量地提升樹突的生長并且增加突觸發(fā)生（創(chuàng)造神經(jīng)細(xì)胞之間的聯(lián)系）。這個過程可能會增強(qiáng)記憶或者允許老鼠通過重新修復(fù)受損的神經(jīng)回路來重新獲得失去的記憶,。“我們相信記憶痕跡仍在那兒,，但因神經(jīng)回路遭到破壞，動物無法找回記憶,。”（生物谷Bioon.com）
生物谷推薦原始出處：
Neuron, Volume 60, Issue 5, 803-817, 10 December 2008
Deregulation of HDAC1 by p25/Cdk5 in Neurotoxicity
Dohoon Kim1,2,Christopher L. Frank1,2,Matthew M. Dobbin1,Rachel K. Tsunemoto1,Weihong Tu3,Peter L. Peng3,Ji-Song Guan1,Byung-Hoon Lee1,Lily Y. Moy1,Paola Giusti1,Nisha Broodie1,Ralph Mazitschek4,Ivanna Delalle1,Stephen J. Haggarty4,5,Rachael L. Neve6,YouMing Lu3andLi-Huei Tsai1,4,,
1 Howard Hughes Medical Institute, Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
2 Division of Medical Sciences, Harvard Medical School, Boston, MA 02120, USA
3 Burnett College of Biomedical Sciences, University of Central Florida, Orlando, FL 32826, USA
4 Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard University, Cambridge, MA 02142, USA
5 Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA
6 Department of Psychiatry, Harvard Medical School, McLean Hospital, Belmont, MA 02478, USA
Aberrant cell-cycle activity and DNA damage are emerging as important pathological components in various neurodegenerative conditions. However, their underlying mechanisms are poorly understood. Here, we show that deregulation of histone deacetylase 1 (HDAC1) activity by p25/Cdk5 induces aberrant cell-cycle activity and double-strand DNA breaks leading to neurotoxicity. In a transgenic model for neurodegeneration, p25/Cdk5 activity elicited cell-cycle activity and double-strand DNA breaks that preceded neuronal death. Inhibition of HDAC1 activity by p25/Cdk5 was identified as an underlying mechanism for these events, and HDAC1 gain of function provided potent protection against DNA damage and neurotoxicity in cultured neurons and an invivo model for ischemia. Our findings outline a pathological signaling pathway illustrating the importance of maintaining HDAC1 activity in the adult neuron. This pathway constitutes a molecular link between aberrant cell-cycle activity and DNA damage and isa potential target for therapeutics against diseases and conditions involving neuronal death.
