RNA-binding proteins with prion-like domains in ALS and FTLD-U
RNA-binding proteins with prion-like domains in ALS and FTLD-U
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DOI：
10.4161/pri.5.3.17230
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发表时间：
2011-07-01
期刊：
影响因子：
2.3
通讯作者：
Shorter, James
中科院分区：
文献类型：
--
作者：
Gitler, Aaron D.;Shorter, James
肌萎缩性侧索硬化症（ALS，也称为Lou Gehrig氏病）是一种令人衰弱的致命神经退行性疾病，破坏了上运动神经元和下运动神经元。 ALS的原因知之甚少。最近出现了ALS中RNA结合蛋白和RNA代谢的核心作用。 RNA结合蛋白TDP-43和FUS是在ALS患者的运动神经元中发现的细胞质夹杂物的主要成分，而TDP-43和FUS中的突变与家族性和零星ALS有关。病理和遗传学还将TDP-43和FUS与额颞Lobar变性与泛素阳性夹杂物（FTLD-U）联系起来。尚不清楚FUS聚集和毒性的机制是否与TDP-43的机制相似或不同。为了解决这个问题，我们采用了酵母模型和纯蛋白质生物化学来定义TDP-43和FUS聚集和毒性的机制，并确定与人类疾病相关的遗传修饰剂。我们已经确定了FUS和TDP-43中类似prion的领域，并提供了证据表明这些域是聚集所必需的。我们的研究定义了两种蛋白质之间的关键相似性以及重要差异。总体而言，我们的发现使我们提出FUS和TDP-43虽然相似的RNA结合蛋白，但可能通过不同的机制进行聚集并赋予疾病表型。
Amyotrophic lateral sclerosis (ALS, also known as Lou Gehrig's disease) is a debilitating and universally fatal neurodegenerative disease that devastates upper and lower motor neurons. The causes of ALS are poorly understood. A central role for RNA-binding proteins and RNA metabolism in ALS has recently emerged. The RNA-binding proteins TDP-43 and FUS are principal components of cytoplasmic inclusions found in motor neurons of ALS patients and mutations in TDP-43 and FUS are linked to familial and sporadic ALS. Pathology and genetics also connect TDP-43 and FUS with frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U). It was unknown whether mechanisms of FUS aggregation and toxicity were similar or different to those of TDP-43. To address this issue, we have employed yeast models and pure protein biochemistry to define mechanisms underlying TDP-43 and FUS aggregation and toxicity, and to identify genetic modifiers relevant to human disease. We have identified prion-like domains in FUS and TDP-43 and provide evidence that these domains are required for aggregation. Our studies have defined key similarities as well as important differences between the two proteins. Collectively, our findings lead us to suggest that FUS and TDP-43, though similar RNA-binding proteins, likely aggregate and confer disease phenotypes via distinct mechanisms.