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Inside out: the role of nucleocytoplasmic transport in ALS and FTLD.
Acta Neuropathologica ( IF 12.7 ) Pub Date : 2016-06-09 , DOI: 10.1007/s00401-016-1586-5
Steven Boeynaems 1, 2 , Elke Bogaert 1, 2 , Philip Van Damme 1, 2 , Ludo Van Den Bosch 1, 2, 3
Affiliation  

Neurodegenerative diseases are characterized by the presence of protein inclusions with a different protein content depending on the type of disease. Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are no exceptions to this common theme. In most ALS and FTLD cases, the predominant pathological species are RNA-binding proteins. Interestingly, these proteins are both depleted from their normal nuclear localization and aggregated in the cytoplasm. This key pathological feature has suggested a potential dual mechanism with both nuclear loss of function and cytoplasmic gain of function being at play. Yet, why and how this pathological cascade is initiated in most patients, and especially sporadic cases, is currently unresolved. Recent breakthroughs in C9orf72 ALS/FTLD disease models point at a pivotal role for the nuclear transport system in toxicity. To address whether defects in nuclear transport are indeed implicated in the disease, we reviewed two decades of ALS/FTLD literature and combined this with bioinformatic analyses. We find that both RNA-binding proteins and nuclear transport factors are key players in ALS/FTLD pathology. Moreover, our analyses suggest that disturbances in nucleocytoplasmic transport play a crucial initiating role in the disease, by bridging both nuclear loss and cytoplasmic gain of functions. These findings highlight this process as a novel and promising therapeutic target for ALS and FTLD.

中文翻译:

由内而外:核质运输在ALS和FTLD中的作用。

神经退行性疾病的特征在于存在取决于疾病类型的具有不同蛋白质含量的蛋白质包裹体。肌萎缩性侧索硬化症(ALS)和额颞叶变性(FTLD)也不例外。在大多数ALS和FTLD病例中,主要病理物种是RNA结合蛋白。有趣的是,这些蛋白质都从其正常的核定位中耗尽并且聚集在细胞质中。这个关键的病理学特征提示了潜在的双重机制,其中功能的核丧失和功能的细胞质获得均在起作用。然而,目前尚不清楚为什么在大多数患者中,特别是在散发性患者中,这种病理级联的起因和方式。C9orf72 ALS / FTLD疾病模型的最新突破指出了核转运系统在毒性中的关键作用。为了解决核运输缺陷是否确实与疾病有关,我们回顾了ALS / FTLD的二十年文献,并将其与生物信息学分析相结合。我们发现,RNA结合蛋白和核转运因子都是ALS / FTLD病理学的关键因素。此外,我们的分析表明,通过弥合核丧失和功能的细胞质获得,核质运输中的障碍在疾病中起着至关重要的起因。这些发现突显了该过程是ALS和FTLD的一种新颖且有希望的治疗靶标。我们回顾了20年的ALS / FTLD文献,并将其与生物信息学分析相结合。我们发现,RNA结合蛋白和核转运因子都是ALS / FTLD病理学的关键因素。此外,我们的分析表明,通过弥合核丧失和功能的细胞质获得,核质运输中的紊乱在疾病中起着至关重要的起因。这些发现突显了该过程是ALS和FTLD的一种新颖且有希望的治疗靶标。我们回顾了20年的ALS / FTLD文献,并将其与生物信息学分析相结合。我们发现,RNA结合蛋白和核转运因子都是ALS / FTLD病理学的关键因素。此外,我们的分析表明,通过弥合核丧失和功能的细胞质获得,核质运输中的紊乱在疾病中起着至关重要的起因。这些发现突显了该过程是ALS和FTLD的一种新颖且有希望的治疗靶标。
更新日期:2016-06-06
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