新基因Rps23r1可治疗阿尔茨海默氏症(Alzheimer's Disease)
β淀粉样蛋白和T蛋白在阿尔茨海默氏症中扮演着关键角色。大脑中β淀粉样蛋白产生和积累过多,会形成大量老年斑;T蛋白异常磷酸化,则会引起脑细胞内的神经原纤维缠结。而大量老年斑和神经原纤维缠结,正是阿尔茨海默氏症患者大脑功能缺损的主要原因。全世界的科学家都在寻找减少这两种蛋白的方法,以作为治疗阿尔茨海默氏症的一种手段。所以,找到一种能够控制两种蛋白的基因显得特别重要。
美国加利福尼亚州伯纳姆医学研究所神经退行性疾病研究项目的执行主管徐浩喜(音译)博士和诺贝尔奖获得者、美国洛克菲勒大学分子细胞神经科学研究室教授保罗·格林加德博士及其他研究人员一道,使用一种称为随机纯合基因扰动的技术寻找可调控淀粉样蛋白产生的基因。他们发现,由Rps23r1基因编码的Rps23r1蛋白可以与一种叫做腺苷酸环化酶的蛋白相互作用,产生一种新蛋白——蛋白激酶A。蛋白激酶A会抑制糖原合酶激酶-3(GSK-3)的活动,从而调控淀粉样蛋白的产生和T蛋白磷酸化。
研究小组还发现,Rps23r1是通过逆转录转座过程被创造出来的。基因通过信使核糖核酸(mRNA)逆转录进行复制,而所得基因副本会被放置在细胞DNA的不同位置。虽然大多数逆转录转座事件都导致非功能性副本——伪基因的出现,但在极少数的情况下,逆转录基因,就像Rps23r1一样,可能会成为有用的功能基因。
“从治疗阿尔茨海默氏症的角度看,如果我们能够在人的大脑细胞中进行这种基因的表达,我们或许就能控制β淀粉样蛋白的积累和T蛋白神经原纤维缠结;而从进化的角度来看,逆转录基因也可以呈现出全新的作用,我们的发现就是一个很好的例子。”徐浩喜博士说。
研究人员已在转基因阿尔茨海默氏症小鼠模型上对Rps23r1减少β淀粉状蛋白水平和T蛋白磷酸化的效果进行了确认。同时他们还确认,Rps23r1是老鼠核糖体蛋白s23(Rps23)基因的一个逆转录版本,而老鼠的Rps23基因几乎与人类Rps23基因完全相同。
原始出处:
Neuron, Volume 64, Issue 3, 328-340, 12 November 2009 doi:10.1016/j.neuron.2009.08.036
A Functional Mouse Retroposed Gene Rps23r1 Reduces Alzheimer's β-Amyloid Levels and Tau Phosphorylation
Yun-wu Zhang1, 2, 8, Shijie Liu2, 8, Xue Zhang2, 8, Wu-Bo Li3, 8, Yaomin Chen2, Xiumei Huang1, 2, Liangwu Sun2, Wenjie Luo4, William J. Netzer4, Richard Threadgill3, Gordon Wiegand3, Ruishan Wang1, 2, Stanley N. Cohen5, Paul Greengard4, Francesca-Fang Liao2, 7, Limin Li3, 6, , and Huaxi Xu2, ,
1 Institute for Biomedical Research and Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Xiamen University, Xiamen 361005, China
2 Neurodegenerative Disease Research Program, Burnham Institute for Medical Research, La Jolla, CA 92037, USA
3 Functional Genetics, Inc., Gaithersburg, MD 20878, USA
4 Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, NY 10065, USA
5 Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA
6 Department of Pathology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100005, China
7 Department of Pharmacology, University of Tennessee Health Science Center College of Medicine, Memphis, TN 38163, USA
Senile plaques consisting of β-amyloid (Aβ) and neurofibrillary tangles composed of hyperphosphorylated tau are major pathological hallmarks of Alzheimer's disease (AD). Elucidation of factors that modulate Aβ generation and tau hyperphosphorylation is crucial for AD intervention. Here, we identify a mouse gene Rps23r1 that originated through retroposition of ribosomal protein S23. We demonstrate that RPS23R1 protein reduces the levels of Aβ and tau phosphorylation by interacting with adenylate cyclases to activate cAMP/PKA and thus inhibit GSK-3 activity. The function of Rps23r1 is demonstrated in cells of various species including human, and in transgenic mice overexpressing RPS23R1. Furthermore, the AD-like pathologies of triple transgenic AD mice were improved and levels of synaptic maker proteins increased after crossing them with Rps23r1 transgenic mice. Our studies reveal a new target/pathway for regulating AD pathologies and uncover a retrogene and its role in regulating protein kinase pathways.
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