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【medical-news】关键在于突触：基因可能阐明神经系统疾患

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At The Synapse: Gene May Shed Light On Neurological Disorders

Article Date: 24 May 2008 - 12:00 PDT

In our brains, where millions of signals move across anetwork of neurons like runners in a relay race, all the critical baton passes take place at synapses. These small gaps between nerve cell endings have to be just the right size for messages to transmit properly. Synapses that grow too large or too small are associated with motor and cognitive impairment, learning and memory difficulties, and other neurological disorders.

In a finding that sheds light on this system, researchers at the University of Wisconsin-Madison describe a gene that controls the proper development of synapses, which could help explain how the process works and why it sometimes goes wrong.

Reporting in the journal Neuron, a team of geneticists in the College of Agricultural and Life Sciences reveal the role of a gene in fruit flies called "nervous wreck" that prevents synapses from overgrowing by damping the effects of a pro-growth signal. Mutations in a human version of "nervous wreck" have been linked to a severe genetic developmental disability, and these findings may eventually help scientists develop treatments for this and other neurological disorders.

"The precise regulation of synaptic growth - not too much and not too little - is a complex biological process," says Kate O'Connor-Giles, a postdoctoral fellow in the genetics department who led the study. "We really need to have a deep understanding of how all the factors involved are working together to develop rational treatments for neurological disorders associated with aberrant synaptic growth."

That's no small task. The brain is the most complex organ in the body, containing a hundred billion nerve cells that branch out and make trillions of connections to other neurons, muscle cells and other cell types. Although an estimated 50 million Americans have some kind of neurological disorder, in the majority of cases the underlying cause is unknown. Improper synaptic growth may explain a portion of these unknown cases.

To crack this complex system, O'Connor-Giles studies a particular type of synapse in fruit flies, known as the neuromuscular junction, which is relatively easy to examine and closely resembles the synapses found in the central nervous system of humans. She works with a particular kind of fly that is unable to produce functional Nervous wreck protein, one of a collection of mutant flies engineered more than 20 years ago by UW-Madison geneticist Barry Ganetzky, in whose laboratory the study was completed with the help of researcher Ling Ling Ho. This collection has been the source of many seminal discoveries in brain science over the years.

Using genetic, biochemical and imaging techniques, O'Connor-Giles showed that the "nervous wreck" protein appears to be part of an important protein complex that helps regulate the density of certain receptors on the surface of the nerve cell at the synapse. In particular, the new findings suggest that the protein complex decommissions receptors that respond to pro-growth signals coming from the well-studied BMP signaling pathway. When the protein complex is working properly, it moves the receptors back inside the nerve cell - where they can no longer receive and respond to the pro-growth signal - at the appropriate time.

"'Nervous wreck' and (the other proteins in the complex) work together to attenuate a positive growth signal," says O'Connor-Giles. "So when it's time for synaptic growth to stop, they are the proteins that ensure the neuron stops listening to the positive growth signal and stops growing. When 'nervous wreck' is absent, you get synapses that are much too large." Problems with other proteins in the complex also lead to synaptic overgrowth in fruit flies and, O'Connor-Giles predicts, may contribute to developmental disabilities in humans as well.

Although her work was done in synapses undergoing initial formation, these findings likely apply to adult brain cells, too. Inside fully formed brains, neural connections grow and change over time in response to experiences, a process called plasticity.

"The presumption is that the same mechanisms that are at play during the initial formation of synapses are then recruited later in life when these synapses need to be modified in response to experience or injury," says O'Connor-Giles. "So by understanding the initial development of synapses, we may also be getting at the molecular mechanisms underlying plasticity."

These findings add to the big picture of how synaptic growth works, a picture that in the long run will help scientists develop treatments for various neurological disorders.

"Being able to manipulate synaptic growth is going to be crucial for treating traumatic spinal chord injuries," says O'Connor-Giles. "It's also going to be important for treating a broad array of other disorders, including epilepsy and developmental disabilities."
http://www.medicalnewstoday.com/articles/108560.php

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关键在于突触：基因可能阐明神经系统疾患

（《今日医学新闻》网络版2008年5月24日报道）

在我们的大脑中，数百万的信号就象接力赛运动员那样在由神经元组成的网络上飞奔，所有关键性的接力棒传递都在突触上完成。这些介于神经细胞终端之间的微小间隙必须大小合适才能够使信息得以正确传送。过大或过小的突触均可产生运动与认知障碍、学习和记忆困难以及其它神经系统失调。

在一项对神经系统疾病有着启导意义的发现中，威斯康星－麦迪逊大学的研究者形容了一个控制突触适度发育的基因可能有助于解释其工作的过程及其有时出错的原因。

研究报告刊登于《神经元》杂志，一个由农业与生命科学学院基因学家组成的研究团队揭示了果蝇中的一个被称为“神经终结者”的基因，该基因可通过阻尼有利生长的信号来防止突触过度生长。人类“神经终结者”基因的突变与重度遗传性发育残疾相关。这些发现可能最终有助于科学家研发出针对此种残疾及其它神经系统障碍的疗法。

“对突触生长精确调节使之大小适中，是个复杂的生物学过程。” 遗传学系的凯特 · 欧库纳 · 姬尔丝（Kate O'Connor-Giles）说道，她是主持此项研究的博士后研究员。“我们实实在在需要深入理解所有这些相关因素的协同作用方式，进而开发出合理的疗法，以解决与异常突触生长有关的神经系统疾病。

这并非小事一桩。大脑是身体中最复杂的器官，包含了一千亿神经细胞，并且各神经细胞的突出部分与其它神经细胞、肌肉细胞及其它细胞类型形成了数以几万亿计的连接。虽然估计有五千万的美国人有某种类型的神经系统疾病，在大部分的病例中，其基本病因尚未能阐明。不合适的突触生长可能解释一部分此种未知的病例。

为解决错综复杂的神经系统问题，凯特 · 欧库纳 · 姬尔丝研究了果蝇中的一种特定的突触类型，即知名的神经肌肉接点。此接点检查相对容易、与在人类中枢神经系统中发现的突触十分相似。她研究的是一种无法产生能起作用的“神经终结者”蛋白的特定类型的果蝇。此果蝇为威斯康星－麦迪逊大学基因学家巴里 · 加内茨基（ Barry Ganetzky）二十多年前利用基因工程改造的一批带变异基因的果蝇中的一种。本研究工作在巴里 · 加内茨基的实验室中完成，并得到研究员Ling Ling Ho的帮助。这批带变异基因的果蝇奠定了多年来在脑科学方面取得的不少开创性成果的基础。

运用遗传、生物化学与成像技术等手段，欧库纳 · 姬尔丝显示了“神经终结者”蛋白看来是一种重要的蛋白质复合物的一部分，该复合物帮助调节突触上神经细胞表面的某种受体的密度。尤其是，新的发现提示该蛋白质复合物使响应来自倍受研究的骨形态发生蛋白信号途径（BMP signaling pathway）的有利于突触生长的信号的受体解除任务。当该蛋白质复合物正常发挥作用时，它使这些受体退回到神经细胞内－在此这些受体无法接受或响应有利突触生长的信号－在合适的时间内。

“神经终结者”与（该复合物内其它蛋白质）协同工作以削弱支持生长的信号，” 欧库纳 · 姬尔丝说。“因此，当突触该停止生长的时候，他们就是保证神经元终止倾听支持生长的信号并终结突触生长的蛋白质。当‘神经终结者’缺席，得到的突触的块头就会太大。” 该复合体中的其它蛋白质出现问题也会导致果蝇突触过度生长，并且，欧库纳 · 姬尔丝预言，出现的问题也可能导致人类的发育性残疾。

虽然她的工作是在正初步成型的突触中完成的，这些发现仍有可能应用于成年脑细胞。在完整成型的大脑中，神经连接会响应经历而随时间生长、变化。经历是一种叫做可塑性的过程。

“假设是：在突触初步成型时发挥作用的相同机制，在后来响应经历或损伤需要这些突触加以修改时，又再次发挥作用。” 欧库纳 · 姬尔丝说。“因此通过理解突触的原始发育情形，我们也可能得以了解作为可塑性基础的分子机制。”

这些发现丰富了有关突触生长原理的知识库。从长远的观点来看，这一知识库将会帮助科学家发展出针对多方面的神经系统疾病的疗法。

“能够操作突触生长，就会成为治疗脊索创伤的关键。 ” 姬尔丝说。“同样对治疗其它范围极广的疾病也很重要，这些疾病包括癫痫与发育性残疾。”

（Docofsoul 翻译于 2008年5月25日）

＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝

＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝＝

At The Synapse: Gene May Shed Light On Neurological Disorders

Article Date: 24 May 2008 - 12:00 PDT

关键在于突触：基因可能阐明神经系统疾患

（《今日医学新闻》网络版2008年5月24日报道）

In our brains, where millions of signals move across anetwork of neurons like runners in a relay race, all the critical baton passes take place at synapses. These small gaps between nerve cell endings have to be just the right size for messages to transmit properly. Synapses that grow too large or too small are associated with motor and cognitive impairment, learning and memory difficulties, and other neurological disorders.

在我们的大脑中，数百万的信号就象接力赛运动员那样在由神经元组成的网络上飞奔，所有关键性的接力棒传递都在突触上完成。这些介于神经细胞终端之间的微小间隙必须大小合适才能够使信息得以正确传送。过大或过小的突触均可产生运动与认知障碍、学习和记忆困难以及其它神经系统失调。

In a finding that sheds light on this system, researchers at the University of Wisconsin-Madison describe a gene that controls the proper development of synapses, which could help explain how the process works and why it sometimes goes wrong.

在一项对神经系统疾病有着启导意义的发现中，威斯康星－麦迪逊大学的研究者形容了一个控制突触适度发育的基因可能有助于解释其工作的过程及其有时出错的原因。

Reporting in the journal Neuron, a team of geneticists in the College of Agricultural and Life Sciences reveal the role of a gene in fruit flies called "nervous wreck" that prevents synapses from overgrowing by damping the effects of a pro-growth signal. Mutations in a human version of "nervous wreck" have been linked to a severe genetic developmental disability, and these findings may eventually help scientists develop treatments for this and other neurological disorders.

研究报告刊登于《神经元》杂志，一个由农业与生命科学学院基因学家组成的研究团队揭示了果蝇中的一个被称为“神经终结者”的基因，该基因可通过阻尼有利生长的信号来防止突触过度生长。人类“神经终结者”基因的突变与重度遗传性发育残疾相关。这些发现可能最终有助于科学家研发出针对此种残疾及其它神经系统障碍的疗法。

"The precise regulation of synaptic growth - not too much and not too little - is a complex biological process," says Kate O'Connor-Giles, a postdoctoral fellow in the genetics department who led the study. "We really need to have a deep understanding of how all the factors involved are working together to develop rational treatments for neurological disorders associated with aberrant synaptic growth."

“对突触生长精确调节使之大小适中，是个复杂的生物学过程。” 遗传学系的凯特 · 欧库纳 · 姬尔丝（Kate O'Connor-Giles）说道，她是主持此项研究的博士后研究员。“我们实实在在需要深入理解所有这些相关因素的协同作用方式，进而开发出合理的疗法，以解决与异常突触生长有关的神经系统疾病。

That's no small task. The brain is the most complex organ in the body, containing a hundred billion nerve cells that branch out and make trillions of connections to other neurons, muscle cells and other cell types. Although an estimated 50 million Americans have some kind of neurological disorder, in the majority of cases the underlying cause is unknown. Improper synaptic growth may explain a portion of these unknown cases.

这并非小事一桩。大脑是身体中最复杂的器官，包含了一千亿神经细胞，并且各神经细胞的突出部分与其它神经细胞、肌肉细胞及其它细胞类型形成了数以几万亿计的连接。虽然估计有五千万的美国人有某种类型的神经系统疾病，在大部分的病例中，其基本病因尚未能阐明。不合适的突触生长可能解释一部分此种未知的病例。

To crack this complex system, O'Connor-Giles studies a particular type of synapse in fruit flies, known as the neuromuscular junction, which is relatively easy to examine and closely resembles the synapses found in the central nervous system of humans. She works with a particular kind of fly that is unable to produce functional Nervous wreck protein, one of a collection of mutant flies engineered more than 20 years ago by UW-Madison geneticist Barry Ganetzky, in whose laboratory the study was completed with the help of researcher Ling Ling Ho. This collection has been the source of many seminal discoveries in brain science over the years.

为解决错综复杂的神经系统问题，凯特 · 欧库纳 · 姬尔丝研究了果蝇中的一种特定的突触类型，即知名的神经肌肉接点。此接点检查相对容易、与在人类中枢神经系统中发现的突触十分相似。她研究的是一种无法产生能起作用的“神经终结者”蛋白的特定类型的果蝇。此果蝇为威斯康星－麦迪逊大学基因学家巴里 · 加内茨基（ Barry Ganetzky）二十多年前利用基因工程改造的一批带变异基因的果蝇中的一种。本研究工作在巴里 · 加内茨基的实验室中完成，并得到研究员Ling Ling Ho的帮助。这批带变异基因的果蝇奠定了多年来在脑科学方面取得的不少开创性成果的基础。

Using genetic, biochemical and imaging techniques, O'Connor-Giles showed that the "nervous wreck" protein appears to be part of an important protein complex that helps regulate the density of certain receptors on the surface of the nerve cell at the synapse. In particular, the new findings suggest that the protein complex decommissions receptors that respond to pro-growth signals coming from the well-studied BMP signaling pathway. When the protein complex is working properly, it moves the receptors back inside the nerve cell - where they can no longer receive and respond to the pro-growth signal - at the appropriate time.

运用遗传、生物化学与成像技术等手段，欧库纳 · 姬尔丝显示了“神经终结者”蛋白看来是一种重要的蛋白质复合物的一部分，该复合物帮助调节突触上神经细胞表面的某种受体的密度。尤其是，新的发现提示该蛋白质复合物使响应来自倍受研究的骨形态发生蛋白信号途径（BMP signaling pathway）的有利于突触生长的信号的受体解除任务。当该蛋白质复合物正常发挥作用时，它使这些受体退回到神经细胞内－在此这些受体无法接受或响应有利突触生长的信号－在合适的时间内。

"'Nervous wreck' and (the other proteins in the complex) work together to attenuate a positive growth signal," says O'Connor-Giles. "So when it's time for synaptic growth to stop, they are the proteins that ensure the neuron stops listening to the positive growth signal and stops growing. When 'nervous wreck' is absent, you get synapses that are much too large." Problems with other proteins in the complex also lead to synaptic overgrowth in fruit flies and, O'Connor-Giles predicts, may contribute to developmental disabilities in humans as well.

“神经终结者”与（该复合物内其它蛋白质）协同工作以削弱支持生长的信号，” 欧库纳 · 姬尔丝说。“因此，当突触该停止生长的时候，他们就是保证神经元终止倾听支持生长的信号并终结突触生长的蛋白质。当‘神经终结者’缺席，得到的突触的块头就会太大。” 该复合体中的其它蛋白质出现问题也会导致果蝇突触过度生长，并且，欧库纳 · 姬尔丝预言，出现的问题也可能导致人类的发育性残疾。

Although her work was done in synapses undergoing initial formation, these findings likely apply to adult brain cells, too. Inside fully formed brains, neural connections grow and change over time in response to experiences, a process called plasticity.

虽然她的工作是在正初步成型的突触中完成的，这些发现仍有可能应用于成年脑细胞。在完整成型的大脑中，神经连接会响应经历而随时间生长、变化。经历是一种叫做可塑性的过程。

"The presumption is that the same mechanisms that are at play during the initial formation of synapses are then recruited later in life when these synapses need to be modified in response to experience or injury," says O'Connor-Giles. "So by understanding the initial development of synapses, we may also be getting at the molecular mechanisms underlying plasticity."

“假设是：在突触初步成型时发挥作用的相同机制，在后来响应经历或损伤需要这些突触加以修改时，又再次发挥作用。” 欧库纳 · 姬尔丝说。“因此通过理解突触的原始发育情形，我们也可能得以了解作为可塑性基础的分子机制。”

These findings add to the big picture of how synaptic growth works, a picture that in the long run will help scientists develop treatments for various neurological disorders.

这些发现丰富了有关突触生长原理的知识库。从长远的观点来看，这一知识库将会帮助科学家发展出针对多方面的神经系统疾病的疗法。

"Being able to manipulate synaptic growth is going to be crucial for treating traumatic spinal chord injuries," says O'Connor-Giles. "It's also going to be important for treating a broad array of other disorders, including epilepsy and developmental disabilities."

“能够操作突触生长，就会成为治疗脊索创伤的关键。 ” 姬尔丝说。“同样对治疗其它范围极广的疾病也很重要，这些疾病包括癫痫与发育性残疾。”

（Docofsoul 翻译于 2008年5月25日）

http://www.medicalnewstoday.com/articles/108560.php

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