研究显示：感染性朊蛋白可在正常脑组织中自发出现

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Infectious Prions Can Arise Spontaneously in Normal Brain Tissue, Study Shows


ScienceDaily (July 27, 2010) — In a startling new study that involved research on both sides of the Atlantic, scientists from The Scripps Research Institute in Florida and the University College London (UCL) Institute of Neurology in England have shown for the first time that abnormal prions, bits of infectious protein devoid of DNA or RNA that can cause fatal neurodegenerative disease, can suddenly erupt from healthy brain tissue.




Artistic rendering of neurons. (Credit: iStockphoto/Andrey Prokhorov)

The catalyst in the study was the metallic surface of simple steel wires. Previous research showed that prions bind readily to these types of surfaces and can initiate infection with remarkable efficiency. Surprisingly, according to the new research, wires coated with uninfected brain homogenate could also initiate prion disease in cell culture, which was transmissible to mice.

The findings are being published in the online edition of the journal Proceedings of the National Academy of Sciences (PNAS).

"Prion diseases such as sporadic Creutzfeldt-Jakob disease in humans or atypical bovine spongiform encephalopathy, a form of mad cow disease, occur rarely and at random," said Charles Weissmann, M.D., Ph.D., chair of Scripps Florida's Department of Infectology, who led the study with John Collinge, head of the Department of Neurodegenerative Disease at UCL Institute of Neurology. "It has been proposed that these events reflect rare, spontaneous formation of prions in brain. Our study offers experimental proof that prions can in fact originate spontaneously, and shows that this event is promoted by contact with steel surfaces."

Infectious prions, which are composed solely of protein, are classified by distinct strains, originally characterized by their incubation time and the disease they cause. These toxic prions have the ability to reproduce, despite the fact that they contain no nucleic acid genome.

Mammalian cells normally produce harmless cellular prion protein (PrPC). Following prion infection, the abnormal or misfolded prion protein (PrPSc) converts PrPC into a likeness of itself, by causing it to change its conformation or shape. The end-stage consists of large aggregates of these misfolded proteins, which cause massive tissue and cell damage.

A Highly Sensitive Test

In the new study, the scientists used the Scrapie Cell Assay, a test originally created by Weissmann that is highly sensitive to minute quantities of prions.

Using the Scrapie Cell Assay to measure infectivity of prion-coated wires, the team observed several unexpected instances of infectious prions in control groups where metal wires had been exposed only to uninfected normal mouse brain tissue. In the current study, this phenomenon was investigated in rigorous and exhaustive control experiments specifically designed to exclude prion contamination. Weissmann and his colleagues in London found that when normal prion protein is coated onto steel wires and brought into contact with cultured cells, a small but significant proportion of the coated wires cause prion infection of the cells -- and when transferred to mice, they continue to spawn the disease.

Weissmann noted that an alternative interpretation of the results is that infectious prions are naturally present in the brain at levels not detectable by conventional methods, and are normally destroyed at the same rate they are created. If that is the case, he noted, metal surfaces could be acting to concentrate the infectious prions to the extent that they became quantifiable by the team's testing methods.

The first author of the study, "Spontaneous Generation of Mammalian Prions," is Julie Edgeworth of the UCL Institute of Neurology. Other authors of the study include Nathalie Gros, Jack Alden, Susan Joiner, Jonathan D.F. Wadsworth, Jackie Linehan, Sebastian Brandner, and Graham S. Jackson, also of the UCL Institute of Neurology.

The study was supported by the U.K. Medical Research Council.

《每日科学》2010年7月27日报道 —— 从大西洋的两岸同时传来了一个令人震惊的消息：来自佛罗里达州斯克里普斯研究院与伦敦大学学院（UCL）英格兰神经病学研究院的科学家同时显示了异常朊蛋白，即DNA或RNA缺如的感染性蛋白质小块，可从健康的脑组织中突然爆发。

本研究所用的催化剂是简简单单的不锈钢丝的金属表面。此前研究显示朊蛋白可便捷地与这些表面类型结合并以不同寻常的效率启动感染过程。令人惊讶的是，根据这项新的研究，用未感染过的脑组织均浆包被的金属丝也能够在细胞培养中引发感染性朊蛋白疾病，并可使小鼠感染。

本研究发现目前正发表于《美国国家科学院院刊》（PNAS）在线版。

“人类中发生的诸如散发性克雅氏病或非典型牛海绵状脑病（一种疯牛病）等感染性朊蛋白病极少出现，并且即使出现也是随机的。有建议说这些事件反映了大脑中朊蛋白罕见的、自发的形成情形。我们的研究则提供了实验证据：感染性朊蛋白实际上可自发产生； 并且我们的实验也显示了这一事件可由接触不锈钢表面而引发。” 佛罗里达州斯克里普斯研究院传染病学系系主任、医学博士、哲学博士 Charles Weissmann说。他与伦敦大学学院神经病学研究学院神经退行性疾病系系主任John Collinge共同领导了这项研究。

感染性朊蛋白由纯粹的蛋白质所组成，按不同品系来分类，原来是根据其潜伏时间及其导致的疾病为特征的。这些有毒的感染性朊蛋白虽然不包含核酸染色体组，却有复制生产能力。

哺乳动物细胞在正常情形下产生无害的细胞朊蛋白（PrPC）。在朊蛋白感染的情形下，异常的或错误折叠的朊蛋白（PrPSc）通过改变PrPC的构造或形态将PrPC变为本身的类似物。末期表现为这些错误折叠的蛋白质大量聚集并导致组织与细胞的巨大破坏。

一项高度灵敏的试验

在新的研究中，科学家使用了搔痒病细胞测试法（Scrapie Cell Assay），这是Weissmann原创的测试方法，对微量朊蛋白高度敏感。

通过运用搔痒病细胞试样来测量朊蛋白包被的金属丝的感染性，该研究小组在对照组中观察到了几例始料未及的感染性朊蛋白的情形。之所以始料未及，是因为对照组的金属丝接触的只是未受感染的正常小鼠脑组织！在目前的研究中，为了检验这一现象，特别设计了严格而全面的对照实验以排除可能的朊蛋白污染。Weissmann及其伦敦同事发现：当正常的朊蛋白包被不锈钢丝后再接触培养细胞，所包被的金属丝的一虽小却是显著易见的部分引起了细胞的朊蛋白感染 —— 而当转移给小鼠时，会继续滋生该疾病。
Weissmann说对该结果的另外一种可能的解释是：感染性朊蛋白实际上自然出现于大脑，只是其水平低到用传统方法测不出来而已，并且其被造的速度与被破坏的速率一致。他说如果是这样的话， 金属表面可能让感染性朊蛋白得以聚集，这样他的研究小组所创的测试手段就得以乘机“大显神通”。

该研究论文的标题是：Spontaneous Generation of Mammalian Prions（《哺乳动物朊蛋白的自发性》）。论文第一作者是伦敦大学学院神经病学研究院的ulie Edgeworth。其他作者包括：Nathalie Gros、Jack Alden、 Susan Joiner、Jonathan D.F. Wadsworth、Jackie Linehan、Sebastian Brandner、and Graham S. Jackson，全部是神经病学研究院成员。

本研究得到了英国医学研究委员会的支持。

BAOTIAN

谢谢提供资料.

大自然

从这个研究中是否可理解为：克雅氏病或者类似的脑病，每个人都有发病的先天条件，只是不知什么原因，少不分人打破了平衡而发病。现在是一经发病就是不可逆的，也许随着研究的深入，能够抑制这种不可逆，使这些脑病患者能够得到康复，那就是一个好消息了。