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腾讯登录Nat & Nat Med：鉴别出影响肌萎缩性脊髓侧索硬化症患者存活的关键基因
| 导读 | 近日，来自美国麻省大学医学院（UMMS）的研究者通过研究发现了可以影响肌萎缩性脊髓侧索硬化症（ALS，俗称为路格里克氏病）患者生存时间的关键基因，相关研究成果刊登在了8月26日的国际著名杂志<em>Nature Medicine</em>上，文章中，研究者描述了受体EphA4活性的缺失如何延长ALS患者的寿命，加上UMMS研究小组上个月在<em>Nature&l... |
近日，来自美国麻省大学医学院（UMMS）的研究者通过研究发现了可以影响肌萎缩性脊髓侧索硬化症（ALS，俗称为路格里克氏病）患者生存时间的关键基因，相关研究成果刊登在了8月26日的国际著名杂志<em>Nature Medicine</em>上，文章中，研究者描述了受体EphA4活性的缺失如何延长ALS患者的寿命，加上UMMS研究小组上个月在<em>Nature</em>上发表的文章（该文章中发现了一种新的ALS基因-抑制蛋白1，该基因编码抑制蛋白1），两篇研究成果共同为从分子上理解ALS敏感性和严重性提供了支持。
研究者Robert表示，这些研究成果令我们异常激动，因为其揭示了EphA4的抑制或许是治疗ALS的一种方法。ALS是一种严重的神经变性疾病，可以影响中枢神经系统的运动神经元的功能。随着运动神经元功能丧失，大脑向机体肌肉传输信号的能力就会降低，这将会导致随意肌运动能力的缺失，严重者可引发中风以及最终呼吸衰竭。目前促发ALS的原因尚不清楚，而且有将近10%的病例是遗传的。尽管研究者发现了一些引发遗传或者促使家族性疾病的基因，但是还有大约50%的病症的遗传原因尚不清楚，而且没有有效的治疗方法。
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研究者通过对斑马鱼进行研究，屏蔽其体内ALS突变基因SOD1的负面作用，研究小组发现了EphA4可以作为ALS的修饰工具，在ALS小鼠中进一步研究发现，EphA4的失活可以使小鼠生存时间延长。
研究者Robberecht博士表示，在ALS患者体内细胞中通过关闭EphA4的功能将会有效减缓ALS疾病的发病病程，而且通过抑制EphA4的功能或许也是将来治疗ALS的一种新的疗法。
在Nature的文章中，研究者发现的抑制蛋白1可以和EphA4一起作用来控制运动神经末梢的生长。实际上，一个信号路径最顶端和最低端的基因突变往往可以影响ALS的发展。最后研究者希望他们的研究成果可以为未来开发ALS新型疗法提供帮助。
编译自：<a title="" href="http://www.sciencedaily.com/releases/2012/08/120826143617.htm" target="_blank">Scientists Identify New Gene That Influences Survival in Amyotrophic Lateral Sclerosis</a>
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<img src="http://www.bioon.com/biology/UploadFiles/201208/2012082722145454.jpg" alt="" width="113" height="149" border="0" />
<a title="" href="http://dx.doi.org/doi:10.1038/nature11280" target="_blank">doi:10.1038/nature11280</a>
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<br/><strong>Mutations in the profilin 1 gene cause familial amyotrophic lateral sclerosis</strong><br/>
Chi-Hong Wu, Claudia Fallini, Nicola Ticozzi, Pamela J. Keagle, Peter C. Sapp, Katarzyna Piotrowska, Patrick Lowe, Max Koppers, Diane McKenna-Yasek, Desiree M. Baron, Jason E. Kost, Paloma Gonzalez-Perez, Andrew D. Fox, Jenni Adams, Franco Taroni, Cinzia Tiloca, Ashley Lyn Leclerc, Shawn C. Chafe, Dev Mangroo, Melissa J. Moore, Jill A. Zitzewitz, Zuo-Shang Xu, Leonard H. van den Berg, Jonathan D. Glass, Gabriele Siciliano et al.
Amyotrophic lateral sclerosis (ALS) is a late-onset neurodegenerative disorder resulting from motor neuron death. Approximately 10% of cases are familial (FALS), typically with a dominant inheritance mode. Despite numerous advances in recent years1, 2, 3, 4, 5, 6, 7, 8, 9, nearly 50% of FALS cases have unknown genetic aetiology. Here we show that mutations within the profilin 1 (PFN1) gene can cause FALS. PFN1 is crucial for the conversion of monomeric (G)-actin to filamentous (F)-actin. Exome sequencing of two large ALS families showed different mutations within the PFN1 gene. Further sequence analysis identified 4 mutations in 7 out of 274 FALS cases. Cells expressing PFN1 mutants contain ubiquitinated, insoluble aggregates that in many cases contain the ALS-associated protein TDP-43. PFN1 mutants also display decreased bound actin levels and can inhibit axon outgrowth. Furthermore, primary motor neurons expressing mutant PFN1 display smaller growth cones with a reduced F/G-actin ratio. These observations further document that cytoskeletal pathway alterations contribute to ALS pathogenesis.
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<img src="http://www.bioon.com/biology/UploadFiles/201208/2012082722165803.jpg" alt="" width="113" height="149" border="0" />
<a title="" href="http://dx.doi.org/doi:10.1038/nm.2901" target="_blank">doi:10.1038/nm.2901</a>
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<br/><strong>EPHA4 is a disease modifier of amyotrophic lateral sclerosis in animal models and in humans</strong><br/>
Annelies Van Hoecke,1, 2 Lies Schoonaert,1, 2 Robin Lemmens,1, 2, 3 Mieke Timmers,1, 2 Kim A Staats,1, 2 Angela S Laird,4 Elke Peeters,3 Thomas Philips,1, 2 An Goris,5 Bénédicte Dubois,3, 5 Peter M Andersen,6 Ammar Al-Chalabi,7 Vincent Thijs,1, 2, 3 Ann M Turnley,8 Paul W van Vught,9 Jan H Veldink,9 Orla Hardiman,10 Ludo Van Den Bosch,1, 2 Paloma Gonzalez-Perez,11 Philip Van Damme,1, 2, 3 Robert H Brown Jr,11 Leonard H van den Berg9 & Wim Robberecht1, 2, 3
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease affecting motor neurons. Disease onset and progression are variable, with survival ranging from months to decades. Factors underlying this variability may represent targets for therapeutic intervention. Here, we have screened a zebrafish model of ALS and identified Epha4, a receptor in the ephrin axonal repellent system, as a modifier of the disease phenotype in fish, rodents and humans. Genetic as well as pharmacological inhibition of Epha4 signaling rescues the mutant SOD1 phenotype in zebrafish and increases survival in mouse and rat models of ALS. Motor neurons that are most vulnerable to degeneration in ALS express higher levels of Epha4, and neuromuscular re-innervation by axotomized motor neurons is inhibited by the presence of Epha4. In humans with ALS, EPHA4 expression inversely correlates with disease onset and survival, and loss-of-function mutations in EPHA4 are associated with long survival. Furthermore, we found that knockdown of Epha4 also rescues the axonopathy induced by expression of mutant TAR DNA-binding protein 43 (TDP-43), another protein causing familial ALS, and the axonopathy induced by knockdown of survival of motor neuron 1, a model for spinomuscular atrophy. This suggests that Epha4 generically modulates the vulnerability of (motor) neurons to axonal degeneration and may represent a new target for therapeutic intervention.
<br/>来源：生物谷
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研究者Robert表示，这些研究成果令我们异常激动，因为其揭示了EphA4的抑制或许是治疗ALS的一种方法。ALS是一种严重的神经变性疾病，可以影响中枢神经系统的运动神经元的功能。随着运动神经元功能丧失，大脑向机体肌肉传输信号的能力就会降低，这将会导致随意肌运动能力的缺失，严重者可引发中风以及最终呼吸衰竭。目前促发ALS的原因尚不清楚，而且有将近10%的病例是遗传的。尽管研究者发现了一些引发遗传或者促使家族性疾病的基因，但是还有大约50%的病症的遗传原因尚不清楚，而且没有有效的治疗方法。
<!--more-->
研究者通过对斑马鱼进行研究，屏蔽其体内ALS突变基因SOD1的负面作用，研究小组发现了EphA4可以作为ALS的修饰工具，在ALS小鼠中进一步研究发现，EphA4的失活可以使小鼠生存时间延长。
研究者Robberecht博士表示，在ALS患者体内细胞中通过关闭EphA4的功能将会有效减缓ALS疾病的发病病程，而且通过抑制EphA4的功能或许也是将来治疗ALS的一种新的疗法。
在Nature的文章中，研究者发现的抑制蛋白1可以和EphA4一起作用来控制运动神经末梢的生长。实际上，一个信号路径最顶端和最低端的基因突变往往可以影响ALS的发展。最后研究者希望他们的研究成果可以为未来开发ALS新型疗法提供帮助。
编译自：<a title="" href="http://www.sciencedaily.com/releases/2012/08/120826143617.htm" target="_blank">Scientists Identify New Gene That Influences Survival in Amyotrophic Lateral Sclerosis</a>
<div id="ztload">
<div>
<div>
<img src="http://www.bioon.com/biology/UploadFiles/201208/2012082722145454.jpg" alt="" width="113" height="149" border="0" />
<a title="" href="http://dx.doi.org/doi:10.1038/nature11280" target="_blank">doi:10.1038/nature11280</a>
PMC:
PMID:
</div>
<div>
<br/><strong>Mutations in the profilin 1 gene cause familial amyotrophic lateral sclerosis</strong><br/>
Chi-Hong Wu, Claudia Fallini, Nicola Ticozzi, Pamela J. Keagle, Peter C. Sapp, Katarzyna Piotrowska, Patrick Lowe, Max Koppers, Diane McKenna-Yasek, Desiree M. Baron, Jason E. Kost, Paloma Gonzalez-Perez, Andrew D. Fox, Jenni Adams, Franco Taroni, Cinzia Tiloca, Ashley Lyn Leclerc, Shawn C. Chafe, Dev Mangroo, Melissa J. Moore, Jill A. Zitzewitz, Zuo-Shang Xu, Leonard H. van den Berg, Jonathan D. Glass, Gabriele Siciliano et al.
Amyotrophic lateral sclerosis (ALS) is a late-onset neurodegenerative disorder resulting from motor neuron death. Approximately 10% of cases are familial (FALS), typically with a dominant inheritance mode. Despite numerous advances in recent years1, 2, 3, 4, 5, 6, 7, 8, 9, nearly 50% of FALS cases have unknown genetic aetiology. Here we show that mutations within the profilin 1 (PFN1) gene can cause FALS. PFN1 is crucial for the conversion of monomeric (G)-actin to filamentous (F)-actin. Exome sequencing of two large ALS families showed different mutations within the PFN1 gene. Further sequence analysis identified 4 mutations in 7 out of 274 FALS cases. Cells expressing PFN1 mutants contain ubiquitinated, insoluble aggregates that in many cases contain the ALS-associated protein TDP-43. PFN1 mutants also display decreased bound actin levels and can inhibit axon outgrowth. Furthermore, primary motor neurons expressing mutant PFN1 display smaller growth cones with a reduced F/G-actin ratio. These observations further document that cytoskeletal pathway alterations contribute to ALS pathogenesis.
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</div>
<div id="ztload">
<div>
<div>
<img src="http://www.bioon.com/biology/UploadFiles/201208/2012082722165803.jpg" alt="" width="113" height="149" border="0" />
<a title="" href="http://dx.doi.org/doi:10.1038/nm.2901" target="_blank">doi:10.1038/nm.2901</a>
PMC:
PMID:
</div>
<div>
<br/><strong>EPHA4 is a disease modifier of amyotrophic lateral sclerosis in animal models and in humans</strong><br/>
Annelies Van Hoecke,1, 2 Lies Schoonaert,1, 2 Robin Lemmens,1, 2, 3 Mieke Timmers,1, 2 Kim A Staats,1, 2 Angela S Laird,4 Elke Peeters,3 Thomas Philips,1, 2 An Goris,5 Bénédicte Dubois,3, 5 Peter M Andersen,6 Ammar Al-Chalabi,7 Vincent Thijs,1, 2, 3 Ann M Turnley,8 Paul W van Vught,9 Jan H Veldink,9 Orla Hardiman,10 Ludo Van Den Bosch,1, 2 Paloma Gonzalez-Perez,11 Philip Van Damme,1, 2, 3 Robert H Brown Jr,11 Leonard H van den Berg9 & Wim Robberecht1, 2, 3
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease affecting motor neurons. Disease onset and progression are variable, with survival ranging from months to decades. Factors underlying this variability may represent targets for therapeutic intervention. Here, we have screened a zebrafish model of ALS and identified Epha4, a receptor in the ephrin axonal repellent system, as a modifier of the disease phenotype in fish, rodents and humans. Genetic as well as pharmacological inhibition of Epha4 signaling rescues the mutant SOD1 phenotype in zebrafish and increases survival in mouse and rat models of ALS. Motor neurons that are most vulnerable to degeneration in ALS express higher levels of Epha4, and neuromuscular re-innervation by axotomized motor neurons is inhibited by the presence of Epha4. In humans with ALS, EPHA4 expression inversely correlates with disease onset and survival, and loss-of-function mutations in EPHA4 are associated with long survival. Furthermore, we found that knockdown of Epha4 also rescues the axonopathy induced by expression of mutant TAR DNA-binding protein 43 (TDP-43), another protein causing familial ALS, and the axonopathy induced by knockdown of survival of motor neuron 1, a model for spinomuscular atrophy. This suggests that Epha4 generically modulates the vulnerability of (motor) neurons to axonal degeneration and may represent a new target for therapeutic intervention.
<br/>来源：生物谷
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