ALS病易感基因ATXN2，TDP-43/ataxin-2互动是治疗干预的一个可能目标

雪茄客

“肌萎缩性侧索硬化症” (ALS)也被称为“Lou Gehrig’s症”，它是一种常见的成人型神经退行性疾病，是不可治愈的。ALS大部分是零星发生的，但约有10%的病例也有一个家族成分，最常见的是SOD1（超氧化物岐化酶）基因。然而SOD1突变只占全部病例的约2%，所以寻找其他ALS风险因子的工作还在继续。

蛋白TDP-43被认为在ALS发病中扮演一个角色，但尚未确定(2011年,美国宾夕法尼亚大学医学院神经退行性疾病研究中心的科学家通过研究，已经找到解释TDP-43蛋白发生变异时是如何导致神经细胞死亡的直接证据)；

Elden等人发现，ataxin-2（一种多谷氨酰胺(polyQ)蛋白，在2-型脊髓小脑萎缩症中发生突变）在动物和细胞模型中是TDP-43毒性的一个强效修饰因子。对915个人所做的DNA分析显示，ATXN2是一个相对比较常见的ALS病易感基因，占ALS病例的近4.7%。这些发现表明，TDP-43/ataxin-2互动是治疗干预的一个可能目标。（生物谷Bioon.com）

生物谷推荐原文出处：

Nature doi:10.1038/nature09320  

Ataxin-2 intermediate-length polyglutamine expansions are associated with increased risk for ALS

Andrew C. Elden,Hyung-Jun Kim,Michael P. Hart,Alice S. Chen-Plotkin,Brian S. Johnson,Xiaodong Fang,Maria Armakola,Felix Geser,Robert Greene,Min Min Lu,Arun Padmanabhan,Dana Clay-Falcone,Leo McCluskey,Lauren Elman,Denise Juhr,Peter J. Gruber,Udo Rüb,Georg Auburger,John Q. Trojanowski,Virginia M.-Y. Lee,Vivianna M. Van Deerlin,Nancy M. Bonini& Aaron D. Gitler

The causes of amyotrophic lateral sclerosis (ALS), a devastating human neurodegenerative disease, are poorly understood, although the protein TDP-43 has been suggested to have a critical role in disease pathogenesis. Here we show that ataxin 2 (ATXN2), a polyglutamine (polyQ) protein mutated in spinocerebellar ataxia type 2, is a potent modifier of TDP-43 toxicity in animal and cellular models. ATXN2 and TDP-43 associate in a complex that depends on RNA. In spinal cord neurons of ALS patients, ATXN2 is abnormally localized; likewise, TDP-43 shows mislocalization in spinocerebellar ataxia type 2. To assess the involvement of ATXN2 in ALS, we analysed the length of the polyQ repeat in the ATXN2 gene in 915 ALS patients. We found that intermediate-length polyQ expansions (27–33 glutamines) in ATXN2 were significantly associated with ALS. These data establish ATXN2 as a relatively common ALS susceptibility gene. Furthermore, these findings indicate that the TDP-43–ATXN2 interaction may be a promising target for therapeutic intervention in ALS and other TDP-43 proteinopathies.

http://www.bioon.com/biology/genetics/452690.shtml

优雅

SOD1;TDP-43;FUS都是常见基因突变位点

litianguang

谢谢楼主。