世界生命科学前沿动态周报（七十六）

（5.13-5.26/2012）
美宝国际集团:陶国新 

　　主要内容：首例针对端粒酶的基因治疗使老鼠寿命健康延长24%；维生素K2能够帮助产能不足的线粒体维持正常的ATP产量；持续压制蛋白质翻译造成普里昂蛋白引起的神经变性；皮肤附件的生理再生及其对再生医学生理学的意义；进行糖酵解的少突胶质细胞维护髓鞘和轴突的长期完整性；基因疗法治疗失聪的潜力和局限。

　　焦点动态：首例针对端粒酶的基因治疗使老鼠寿命健康延长24%

1. 首例针对端粒酶的基因治疗使老鼠寿命健康延长24%
【动态】 西班牙科学家最近的研究成功的诱导细胞表达端粒酶，调慢生物钟，在概念上为有效的提高健康寿命的可行且安全的方法提供了证据。 之前有很多研究已经表明通过调节特定基因能够延长包括哺乳动物在内的许多物种的平均寿命，但迄今为止，这些方法都需要从胚胎阶段就永久性的改变动物的基因，这在人类是不可行的。而最近西班牙科学家的研究表明对成年老鼠实施一次基因治疗能够延长其寿命。他们使用了以前从没用于抗衰老的一种基因治疗策略，并发现在老鼠上是安全有效的。他们挑选了一种不复制非致病的去除自身基因的病毒作为载体分别向1年大的老鼠和2年大的老鼠体内送入可在较长时间内表达的老鼠端粒酶逆转录酶（TERT）基因，分别延长老鼠平均寿命达24%和13%，而且明显改善了健康状况，延迟了骨质疏松、胰岛素抗性等衰老相关疾病，同时没有提高患癌风险。
【点评】 尽管上述通过在成年和老年老鼠体内引入端粒酶基因的方法至少在短期内可能无法作为抗衰老的疗法应用于人类，这一思路可能为组织内端粒异常缩短的疾病提供了一种可供选择的治疗方案。

【参考论文】 EMBO Molecular Medicine, 2012 (in press) DOI: 10.1002/emmm.201200245 
Telomerase gene therapy in adult and old mice delays ageing and increases longevity without increasing cancer
Bruno Bernardes de Jesus, Elsa Vera, Kerstin Schneeberger, et al.
A major goal in aging research is to improve health during aging. In the case of mice, genetic manipulations that shorten or lengthen telomeres result, respectively, in decreased or increased longevity. Based on this, we have tested the effects of a telomerase gene therapy in adult (1 year of age) andold (2 years of age) mice. Treatment of 1- and 2-year old mice with an adeno associated virus (AAV) of wide tropism expressing mouse TERT had remarkable beneficial effects on health and fitness, including insulin sensitivity, osteoporosis, neuromuscular coordination and several molecular biomarkers of aging. Importantly, telomerase-treated mice did not develop more cancer than their control littermates, suggesting that the known tumorigenic activity of telomerase is severely decreased when expressed in adult or old organisms using AAV vectors. Finally, telomerase-treated mice, both at 1-year and at 2-year of age, had an increase in median lifespan of 24 and 13%, respectively. These beneficial effects were not observed with a catalytically inactive TERT, demonstrating that they require telomerase activity. Together, these results constitute a proof-of-principle of a role of TERT in delaying physiological aging and extending longevity in normal mice through a telomerase-based treatment, and demonstrate the feasibility of anti-aging gene therapy.

2. 维生素K2能够帮助产能不足的线粒体维持正常的ATP产量
【动态】比利时和美国科学家的一项合作研究最近发现维生素K2能够挽救基因突变造成的线粒体功能障碍，为因为这种线粒体功能障碍造成的帕金森症患者带来了希望。线粒体作为能量工厂提供细胞正常运转所需能量。线粒体通过转运电子产能，而在帕金森患者这一功能被破坏，导致线粒体无法产出足够能量。尽管准确病因还不清楚，最近几年，已发现诸如PINK1 和 Parkin 基因突变存在于帕金森患者体内，二者都会引起线粒体功能减弱。比利时和美国科学家用PINK1 或 Parkin 基因突变的果蝇作为模式生物，发现两种果蝇都失去了飞行能力。进一步的检查发现这些果蝇体内的线粒体就像帕金森患者的一样有功能缺陷，产能减少。当喂给这些果蝇维生素K2后，它们线粒体的能量生产恢复了，提高了飞行能力。研究也证明这种能量生产恢复是因为维生素K2作为电子转运载体促进了线粒体内的电子转运。
【点评】维生素K2作为线粒体内电子载体，能够帮助因基因突变造成产能不足的线粒体维持正常的ATP生产量，也许将来有希望为帕金森患者提供新的治疗方案。

【参考论文】
Science, 2012; DOI:10.1126/science.1218632
Vitamin K2 Is a Mitochondrial Electron Carrier That Rescues Pink1 Deficiency
M. Vos, G. Esposito, J. N. Edirisinghe, et al.
Human UBIAD1 localizes to mitochondria and converts vitamin K1 to vitamin K2. Vitamin K2 is best known as a cofactor in blood coagulation, but in bacteria it is a membrane-bound electron carrier. Whether vitamin K2 exerts a similar carrier function in eukaryotic cells is unknown. We identified Drosophila UBIAD1/Heix as a modifier of pink1, a gene mutated in Parkinson’s disease that affects mitochondrial function. Here, we found that vitamin K2 was necessary and sufficient to transfer electrons in Drosophila mitochondria. Heix mutants showed severe mitochondrial defects that were rescued by vitamin K2, and, similar to ubiquinone, vitamin K2transferred electrons in Drosophila mitochondria, resulting in more efficient adenosine triphosphate (ATP) production. Thus, mitochondrial dysfunction was rescued by vitamin K2 that serves as a mitochondrial electron carrier, helping to maintain normal ATP production.

3. 持续压制蛋白质翻译造成普里昂蛋白引起的神经变性
【动态】目前对于神经变性疾病中神经细胞的死亡原因还很不清楚，许多此类疾病，像老年痴呆、帕金森症和疯牛病都与错误折叠的疾病特异蛋白的积累有关联。这些错误折叠的蛋白水平的上升引起细胞的保护性反应-蛋白去折叠。这一反应途径的影响之一是暂时终止蛋白质翻译。而英国科学家的最新研究发现阮病毒复制过程中的普里昂蛋白的积累会持久压制整体的蛋白质合成，使得阮病毒感染的老鼠神经突触故障、神经元丢失，而促进恢复这些老鼠海马区的蛋白质翻译能够保护神经。鉴于蛋白错误折叠和细胞蛋白去折叠的保护性反应普遍存在与各种神经变性疾病中，他们的结果揭示了调节像翻译控制这样的共同的生化途径而非疾病特异性途径，或许能够发现新的疗法防止神经突触故障和神经元丢失。

【点评】 该研究显示了一种萌芽状态的思路转变即从针对疾病治病到针对调节身体的正常功能治病。也就是说这项研究的研究人员开始意识到通过恢复机体的正常功能来达到去除某些特定疾病也许是一种更好的医学思路。

【参考论文】
Nature, 2012; DOI:10.1038/nature11058
Sustained translational repression by eIF2α-P mediates prion neurodegeneration
Julie A. Moreno, Helois Radford, Diego Peretti, et al. 
The mechanisms leading to neuronal death in neurodegenerative disease are poorly understood. Many of these disorders, including Alzheimer’s, Parkinson’s and prion diseases, are associated with the accumulation of misfolded disease-specific proteins. The unfolded protein response is a protective cellular mechanism triggered by rising levels of misfolded proteins. One arm of this pathway results in the transient shutdown of protein translation, through phosphorylation of the α-subunit of eukaryotic translation initiation factor, eIF2. Activation of the unfolded protein response and/or increased eIF2α-P levels are seen in patients with Alzheimer’s, Parkinson’s and prion diseases, but how this links to neurodegeneration is unknown. Here we show that accumulation of prion protein during prion replication causes persistent translational repression of global protein synthesis by eIF2α-P, associated with synaptic failure and neuronal loss in prion-diseased mice. Further, we show that promoting translational recovery in hippocampi of prion-infected mice is neuroprotective. Overexpression of GADD34, a specific eIF2α-P phosphatase, as well as reduction of levels of prion protein by lentivirally mediated RNA interference, reduced eIF2α-P levels. As a result, both approaches restored vital translation rates during prion disease, rescuing synaptic deficits and neuronal loss, thereby significantly increasing survival. In contrast, salubrinal, an inhibitor of eIF2α-P dephosphorylation, increased eIF2α-P levels, exacerbating neurotoxicity and significantly reducing survival in prion-diseased mice. Given the prevalence of protein misfolding and activation of the unfolded protein response in several neurodegenerative diseases, our results suggest that manipulation of common pathways such as translational control, rather than disease-specific approaches, may lead to new therapies preventing synaptic failure and neuronal loss across the spectrum of these disorders.

4. 皮肤附件的生理再生及其对再生医学生理学的意义
【动态】最近一篇美国英国台湾科学家合作发表的综述文章讨论了皮肤附件的生理再生及其对再生医学生理学的意义。尽管再生医学还是个相对比较新的概念，大家都知道动物能够通过正常的生理再生过程定期重生头发和羽毛。该文章审查了数十篇关于正常生理再生—动物终生具有的再生长而非对损伤的反应—的论文。这种再生在动物生长的不同阶段适时地发生（比如鸟类的换羽毛，小男孩的细软面部毛发在青春期被胡须替代）。这些变化是对像毛囊本身的生理这类内在因素或环境等外在因素的响应，但这些正常变化的内在机制还不清楚。毛囊中的干细胞促进毛发和羽毛的再生，但研究人员现在还不知道如何引导这些细胞形成皮肤附件的正常形态尺寸和定位，也不知道如何让受伤后形成疤痕的人体皮肤再长出毛发。这些未知的知识很可能藏有有价值的线索引导我们了解如何伤后再生更复杂更有价值的结构如手指和脚趾。

【点评】 该综述总结了目前再生生物学的发展和局限，也期待更深入的研究正常的再生生理机制能够帮助在机体受伤后再生出比毛发更复杂的生理结构。他们想到的这些事情在人体再生复原科学的领域里都已成为现实了，尽管更深入的再生机制还需要继续研究。

【参考论文】
Physiology, April 2012 27:61-72 DOI: 10.1152/physiol.00028.2011
Physiological Regeneration of Skin Appendages and Implications for Regenerative Medicine Physiology
Cheng-Ming Chuong, Valerie A. Randall, Randall B. Widelitz, et al.
The concept of regenerative medicine is relatively new, but animals are well known to remake their hair and feathers regularly by normal regenerative physiological processes. Here, we focus on 1) how extrafollicular environments can regulate hair and feather stem cell activities and 2) how different configurations of stem cells can shape organ forms in different body regions to fulfill changing physiological needs.

5. 进行糖酵解的少突胶质细胞维护髓鞘和轴突的长期完整性
【动态】人脑中约1000亿的神经细胞支持我们的思考感觉和行动。这些细胞长的神经纤维即轴突将电信号传递到大脑和身体的远端。这种通讯需要大量的被认为是来自糖的能量。轴突与胶质细胞紧密相连，后者用不导电的髓鞘包绕轴突并支持轴突的长期功能。最近一个国际科研团队发现了一种可能的机制，这些脑中的胶质细胞借以支持轴突并维持轴突的长期生活。少突胶质细胞是中枢神经系统中一组高度特异性的胶质细胞，负责形成富含脂肪的包绕轴突的髓鞘绝缘层，但髓鞘的功能不止是绝缘，它能增加轴突的信号传递速度，减少能量消耗。髓鞘的极度重要性在因绝缘层功能缺陷导致的疾病如多发性硬化中得以体现。而少突胶质细胞的功能也远不止提供髓鞘层。该团队发现健康的胶质细胞是轴突长期功能和存活的无关髓鞘生成的必须因素。胶质细胞参与了神经纤维的能量补给，健康的成熟胶质细胞主要通过糖酵解产生能量，其优势在于糖酵解过程中的代谢产物可以用于髓鞘合成，而且在少突胶质细胞中生成的乳酸能够传给轴突用于轴突自身线粒体的能量生产。 
【点评】 该研究发现的胶质细胞和轴突在生理上的相互配合和协调证明作为机体功能的正常发挥必须整体的配合和协调，不同的结构在不同的生理条件下各自具有维持生命功能正常的重要作用。

【参考论文】
Nature, 2012; DOI: 10.1038/nature11007
Glycolytic oligodendrocytes maintain myelin and long-term axonal integrity
Ursula Fünfschilling, Lotti M. Supplie, Don Mahad, et al. 
Oligodendrocytes, the myelin-forming glial cells of the central nervous system, maintain long-term axonal integrity. However, the underlying support mechanisms are not understood. Here we identify a metabolic component of axon–glia interactions by generating conditional Cox10(protoheme IX farnesyltransferase) mutant mice, in which oligodendrocytes and Schwann cells fail to assemble stable mitochondrial cytochrome coxidase (COX, also known as mitochondrial complex IV). In the peripheral nervous system, Cox10 conditional mutants exhibit severe neuropathy with dysmyelination, abnormal Remak bundles, muscle atrophy and paralysis. Notably, perturbing mitochondrial respiration did not cause glial cell death. In the adult central nervous system, we found no signs of demyelination, axonal degeneration or secondary inflammation. Unlike cultured oligodendrocytes, which are sensitive to COX inhibitors, post-myelination oligodendrocytes survive well in the absence of COX activity. More importantly, by in vivo magnetic resonance spectroscopy, brain lactate concentrations in mutants were increased compared with controls, but were detectable only in mice exposed to volatile anaesthetics. This indicates that aerobic glycolysis products derived from oligodendrocytes are rapidly metabolized within white matter tracts. Because myelinated axons can use lactate when energy-deprived, our findings suggest a model in which axon–glia metabolic coupling serves a physiological function.

6. 基因疗法治疗失聪的潜力和局限
【动态】美国科学家最近发现在年幼老鼠的耳蜗引入Atoh1基因（毛细胞分化因子）能够诱导生长更多的听觉毛细胞。这些新生的毛细胞像正常毛细胞一样产生电信号并与神经细胞相连，但是在老鼠两周大以后青春期之前引入Atoh1基因几乎没有作用。这预示着在成年人应用类似的疗法也不会有效。

【点评】在基因改造的动物模型身上发现的现象并不必然反映在正常动物身上，更不用说与人体的反应有多大相关性。而且从婴幼儿动物进行的基因干预在处理成年动物疾病时也不可行，而且还存在基因干预后的其他不可预料的结果。

【参考论文】
Journal of Neuroscience, 2012; 32 (19): 6699 DOI:10.1523/JNEUROSCI.5420-11.2012
Atoh1 Directs the Formation of Sensory Mosaics and Induces Cell Proliferation in the Postnatal Mammalian Cochlea In Vivo
M. C. Kelly, Q. Chang, A. Pan, X. Lin, P. Chen.

Hearing impairment due to the loss of sensory hair cells is permanent in humans. Considerable interest targets the hair cell differentiation factor Atoh1 as a potential tool with which to promote hair cell regeneration. We generated a novel mouse model to direct the expression of Atoh1 in a spatially and temporally specific manner in the postnatal mammalian cochlea to determine the competency of various types of cochlear epithelial cells for hair cell differentiation. Atoh1 can generate cells in young animals with morphological, molecular, and physiological properties reminiscent of hair cells. This competency is cell type specific and progressively restricted with age. Significantly, Atoh1 induces ectopic sensory patches through Notch signaling to form a cellular mosaic similar to the endogenous sensory epithelia and expansion of the sensory mosaic through the conversion of supporting cells and nonautonomous supporting cell production. Furthermore, Atoh1 also activates proliferation within the normally postmitotic cochlear epithelium. These results provide insight into the potential and limitations of Atoh1-mediated hair cell regeneration.