RNA-binding proteins in neurodegenerative disease: TDP-43 and beyond.
RNA-binding proteins in neurodegenerative disease: TDP-43 and beyond.
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神经退行性疾病中的RNA结合蛋白：TDP-43及以后。
DOI：
10.1002/wrna.111
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发表时间：
2012-03
影响因子：
7.3
通讯作者：
Tibbetts, Randal S.
中科院分区：
文献类型：
--
作者：
Hanson, Keith A.;Kim, Sang Hwa;Tibbetts, Randal S.
神经退行性疾病是一组影响不同神经元群体的不同疾病，其发病和严重程度不同，并且可以是遗传性的或散发性的。大多数这些疾病的一个共同病理特征是在神经元内和周围存在不溶性包涵体，其主要由错误折叠和聚集的蛋白质组成。由于这个原因，神经退行性疾病通常被认为是异常蛋白质加工的病症，其中错误折叠的蛋白质聚集体的累积效应压倒了神经元的蛋白质抑制能力。然而，越来越多的证据表明异常RNA加工在神经退行性疾病中的作用。发现TDP-43（TAR DNA结合蛋白）（一种RNA结合蛋白（RBP））作为散发性肌萎缩性侧索硬化（ALS）患者不溶性聚集体的主要成分，突出了RNA代谢在疾病中的重要性。随后，发现TDP-43和结构相关的RBP，FUS/TLS（在肉瘤中融合/在脂肪肉瘤中翻译）中的遗传突变导致ALS。这些令人兴奋的发现开创了ALS研究的新时代，其中RNA代谢的失调被视为运动神经元退化的主要原因。此外，神经病理学和解剖学上不同的神经退行性疾病显示改变的RNA代谢的事实表明，共同的病理机制可能是许多这些疾病的基础。
Neurodegenerative diseases are a diverse group of disorders that affect different neuron populations, differ in onset and severity, and can be either inherited or sporadic. One common pathological feature of most of these diseases is the presence of insoluble inclusions in and around neurons, which largely consist of misfolded and aggregated protein. For this reason, neurodegenerative diseases are typically thought to be disorders of aberrant protein processing, in which the cumulative effects of misfolded protein aggregates overwhelm the neuron’s proteostatic capacity. However, a growing body of evidence suggests a role for abnormal RNA processing in neurodegenerative disease. The importance of RNA metabolism in disease was highlighted by the discovery of TDP-43 (TAR DNA-binding protein), an RNA-binding protein (RBP), as a primary component of insoluble aggregates in patients with sporadic amyotrophic lateral sclerosis (ALS). Subsequently, inherited mutations in TDP-43 and the structurally related RBP, FUS/TLS (fused in sarcoma/translated in liposarcoma), were found to cause ALS. These exciting findings have ushered in a new era of ALS research in which the deregulation of RNA metabolism is viewed as a central cause of motor neuron deterioration. In addition, the fact that neuropathologically and anatomically distinct neurodegenerative diseases display altered RNA metabolism suggests that common pathologic mechanisms may underlie many of these disorders.
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