Understanding the role of TDP-43 and FUS/TLS in ALS and beyond.
Understanding the role of TDP-43 and FUS/TLS in ALS and beyond.
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DOI：
10.1016/j.conb.2011.05.029
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发表时间：
2011-12
影响因子：
5.7
通讯作者：
Cleveland DW
中科院分区：
文献类型：
--
作者：
Da Cruz S;Cleveland DW
两种DNA/RNA结合蛋白TDP-43和FUS/TLS的显性突变是遗传性肌萎缩性侧索硬化症（ALS）的原因。TDP-43和FUS/TLS具有惊人的结构和功能相似性，这意味着RNA加工的改变是ALS的核心。TDP-43在大脑中三分之一的小鼠和人类mrna中有结合位点，这种结合影响了至少20%的mrna的水平和剪接模式。对啮齿类动物进行疾病建模，发现遗传性ALS的第一个已知原因是普遍表达的超氧化物歧化酶（SOD1）突变，结果显示，突变蛋白获得的一种或多种毒性特性导致了非细胞自主致命的运动神经元疾病。相比之下，TDP-43和FUS/TLS的初始疾病模型产生了高度不同的表型。目前尚不清楚TDP-43和FUS/TLS突变体是由于功能丧失还是毒性增加或两者兼而有之而引起疾病。TDP-43或FUS/TLS错误积累似乎不仅是ALS（几乎在所有疾病中都发现）的核心，而且在更广泛的神经退行性疾病中，包括额叶颞叶痴呆（FTLD-U）和许多阿尔茨海默病或亨廷顿病的例子。(182字)
Dominant mutation in two DNA/RNA binding proteins, TDP-43 and FUS/TLS, are causes of inherited Amyotrophic Lateral Sclerosis (ALS). TDP-43 and FUS/TLS have striking structural and functional similarities, implicating alterations in RNA processing as central in ALS. TDP-43 has binding sites within a third of all mouse and human mRNAs in brain and this binding influences the levels and splicing patterns of at least 20% of those mRNAs. Disease modeling in rodents of the first known cause of inherited ALS – mutation in the ubiquitously expressed superoxide dismutase (SOD1) – has yielded non-cell autonomous fatal motor neuron disease caused by one or more toxic properties acquired by the mutant proteins. In contrast, initial disease modeling for TDP-43 and FUS/TLS has produced highly varied phenotypes. It remains unsettled whether TDP-43 and FUS/TLS mutants provoke disease from a loss of function or gain of toxicity or both. TDP-43 or FUS/TLS misaccumulation seems central not just to ALS (where it is found in almost all instances of disease), but more broadly in neurodegenerative disease, including frontal temporal lobular dementia (FTLD-U) and many examples of Alzheimer’s or Huntington’s disease. (182 words)
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