世界生命科學前沿動態(tài)周報（七十六）

（5.13-5.26/2012）
美寶國際集團:陶國新 

　　主要內容：首例針對端粒酶的基因治療使老鼠壽命健康延長24%；維生素K2能夠幫助產(chǎn)能不足的線粒體維持正常的ATP產(chǎn)量；持續(xù)壓制蛋白質翻譯造成普里昂蛋白引起的神經(jīng)變性；皮膚附件的生理再生及其對再生醫(yī)學生理學的意義；進行糖酵解的少突膠質細胞維護髓鞘和軸突的長期完整性；基因療法治療失聰?shù)臐摿途窒蕖?

　　焦點動態(tài)：首例針對端粒酶的基因治療使老鼠壽命健康延長24%

1. 首例針對端粒酶的基因治療使老鼠壽命健康延長24%
【動態(tài)】 西班牙科學家最近的研究成功的誘導細胞表達端粒酶，調慢生物鐘，在概念上為有效的提高健康壽命的可行且安全的方法提供了證據(jù)。 之前有很多研究已經(jīng)表明通過調節(jié)特定基因能夠延長包括哺乳動物在內的許多物種的平均壽命，但迄今為止，這些方法都需要從胚胎階段就永久性的改變動物的基因，這在人類是不可行的。而最近西班牙科學家的研究表明對成年老鼠實施一次基因治療能夠延長其壽命。他們使用了以前從沒用于抗衰老的一種基因治療策略，并發(fā)現(xiàn)在老鼠上是安全有效的。他們挑選了一種不復制非致病的去除自身基因的病毒作為載體分別向1年大的老鼠和2年大的老鼠體內送入可在較長時間內表達的老鼠端粒酶逆轉錄酶（TERT）基因，分別延長老鼠平均壽命達24%和13%，而且明顯改善了健康狀況，延遲了骨質疏松、胰島素抗性等衰老相關疾病，同時沒有提高患癌風險。
【點評】 盡管上述通過在成年和老年老鼠體內引入端粒酶基因的方法至少在短期內可能無法作為抗衰老的療法應用于人類，這一思路可能為組織內端粒異?？s短的疾病提供了一種可供選擇的治療方案。

【參考論文】 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. 維生素K2能夠幫助產(chǎn)能不足的線粒體維持正常的ATP產(chǎn)量
【動態(tài)】比利時和美國科學家的一項合作研究最近發(fā)現(xiàn)維生素K2能夠挽救基因突變造成的線粒體功能障礙，為因為這種線粒體功能障礙造成的帕金森癥患者帶來了希望。線粒體作為能量工廠提供細胞正常運轉所需能量。線粒體通過轉運電子產(chǎn)能，而在帕金森患者這一功能被破壞，導致線粒體無法產(chǎn)出足夠能量。盡管準確病因還不清楚，最近幾年，已發(fā)現(xiàn)諸如PINK1 和 Parkin 基因突變存在于帕金森患者體內，二者都會引起線粒體功能減弱。比利時和美國科學家用PINK1 或 Parkin 基因突變的果蠅作為模式生物，發(fā)現(xiàn)兩種果蠅都失去了飛行能力。進一步的檢查發(fā)現(xiàn)這些果蠅體內的線粒體就像帕金森患者的一樣有功能缺陷，產(chǎn)能減少。當喂給這些果蠅維生素K2后，它們線粒體的能量生產(chǎn)恢復了，提高了飛行能力。研究也證明這種能量生產(chǎn)恢復是因為維生素K2作為電子轉運載體促進了線粒體內的電子轉運。
【點評】維生素K2作為線粒體內電子載體，能夠幫助因基因突變造成產(chǎn)能不足的線粒體維持正常的ATP生產(chǎn)量，也許將來有希望為帕金森患者提供新的治療方案。

【參考論文】
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. 持續(xù)壓制蛋白質翻譯造成普里昂蛋白引起的神經(jīng)變性
【動態(tài)】目前對于神經(jīng)變性疾病中神經(jīng)細胞的死亡原因還很不清楚，許多此類疾病，像老年癡呆、帕金森癥和瘋牛病都與錯誤折疊的疾病特異蛋白的積累有關聯(lián)。這些錯誤折疊的蛋白水平的上升引起細胞的保護性反應-蛋白去折疊。這一反應途徑的影響之一是暫時終止蛋白質翻譯。而英國科學家的最新研究發(fā)現(xiàn)阮病毒復制過程中的普里昂蛋白的積累會持久壓制整體的蛋白質合成，使得阮病毒感染的老鼠神經(jīng)突觸故障、神經(jīng)元丟失，而促進恢復這些老鼠海馬區(qū)的蛋白質翻譯能夠保護神經(jīng)。鑒于蛋白錯誤折疊和細胞蛋白去折疊的保護性反應普遍存在與各種神經(jīng)變性疾病中，他們的結果揭示了調節(jié)像翻譯控制這樣的共同的生化途徑而非疾病特異性途徑，或許能夠發(fā)現(xiàn)新的療法防止神經(jīng)突觸故障和神經(jīng)元丟失。

【點評】 該研究顯示了一種萌芽狀態(tài)的思路轉變即從針對疾病治病到針對調節(jié)身體的正常功能治病。也就是說這項研究的研究人員開始意識到通過恢復機體的正常功能來達到去除某些特定疾病也許是一種更好的醫(yī)學思路。

【參考論文】
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. 皮膚附件的生理再生及其對再生醫(yī)學生理學的意義
【動態(tài)】最近一篇美國英國臺灣科學家合作發(fā)表的綜述文章討論了皮膚附件的生理再生及其對再生醫(yī)學生理學的意義。盡管再生醫(yī)學還是個相對比較新的概念，大家都知道動物能夠通過正常的生理再生過程定期重生頭發(fā)和羽毛。該文章審查了數(shù)十篇關于正常生理再生—動物終生具有的再生長而非對損傷的反應—的論文。這種再生在動物生長的不同階段適時地發(fā)生（比如鳥類的換羽毛，小男孩的細軟面部毛發(fā)在青春期被胡須替代）。這些變化是對像毛囊本身的生理這類內在因素或環(huán)境等外在因素的響應，但這些正常變化的內在機制還不清楚。毛囊中的干細胞促進毛發(fā)和羽毛的再生，但研究人員現(xiàn)在還不知道如何引導這些細胞形成皮膚附件的正常形態(tài)尺寸和定位，也不知道如何讓受傷后形成疤痕的人體皮膚再長出毛發(fā)。這些未知的知識很可能藏有有價值的線索引導我們了解如何傷后再生更復雜更有價值的結構如手指和腳趾。

【點評】 該綜述總結了目前再生生物學的發(fā)展和局限，也期待更深入的研究正常的再生生理機制能夠幫助在機體受傷后再生出比毛發(fā)更復雜的生理結構。他們想到的這些事情在人體再生復原科學的領域里都已成為現(xiàn)實了，盡管更深入的再生機制還需要繼續(xù)研究。

【參考論文】
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. 進行糖酵解的少突膠質細胞維護髓鞘和軸突的長期完整性
【動態(tài)】人腦中約1000億的神經(jīng)細胞支持我們的思考感覺和行動。這些細胞長的神經(jīng)纖維即軸突將電信號傳遞到大腦和身體的遠端。這種通訊需要大量的被認為是來自糖的能量。軸突與膠質細胞緊密相連，后者用不導電的髓鞘包繞軸突并支持軸突的長期功能。最近一個國際科研團隊發(fā)現(xiàn)了一種可能的機制，這些腦中的膠質細胞借以支持軸突并維持軸突的長期生活。少突膠質細胞是中樞神經(jīng)系統(tǒng)中一組高度特異性的膠質細胞，負責形成富含脂肪的包繞軸突的髓鞘絕緣層，但髓鞘的功能不止是絕緣，它能增加軸突的信號傳遞速度，減少能量消耗。髓鞘的極度重要性在因絕緣層功能缺陷導致的疾病如多發(fā)性硬化中得以體現(xiàn)。而少突膠質細胞的功能也遠不止提供髓鞘層。該團隊發(fā)現(xiàn)健康的膠質細胞是軸突長期功能和存活的無關髓鞘生成的必須因素。膠質細胞參與了神經(jīng)纖維的能量補給，健康的成熟膠質細胞主要通過糖酵解產(chǎn)生能量，其優(yōu)勢在于糖酵解過程中的代謝產(chǎn)物可以用于髓鞘合成，而且在少突膠質細胞中生成的乳酸能夠傳給軸突用于軸突自身線粒體的能量生產(chǎn)。 
【點評】 該研究發(fā)現(xiàn)的膠質細胞和軸突在生理上的相互配合和協(xié)調證明作為機體功能的正常發(fā)揮必須整體的配合和協(xié)調，不同的結構在不同的生理條件下各自具有維持生命功能正常的重要作用。

【參考論文】
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. 基因療法治療失聰?shù)臐摿途窒?
【動態(tài)】美國科學家最近發(fā)現(xiàn)在年幼老鼠的耳蝸引入Atoh1基因（毛細胞分化因子）能夠誘導生長更多的聽覺毛細胞。這些新生的毛細胞像正常毛細胞一樣產(chǎn)生電信號并與神經(jīng)細胞相連，但是在老鼠兩周大以后青春期之前引入Atoh1基因幾乎沒有作用。這預示著在成年人應用類似的療法也不會有效。

【點評】在基因改造的動物模型身上發(fā)現(xiàn)的現(xiàn)象并不必然反映在正常動物身上，更不用說與人體的反應有多大相關性。而且從嬰幼兒動物進行的基因干預在處理成年動物疾病時也不可行，而且還存在基因干預后的其他不可預料的結果。

【參考論文】
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.