Protein Aggregation and Defective RNA Metabolism as Mechanisms for Motor Neuron Damage
Protein Aggregation and Defective RNA Metabolism as Mechanisms for Motor Neuron Damage
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DOI：
10.2174/187152710791292585
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发表时间：
2010-07-01
影响因子：
3
通讯作者：
Silani, V.
中科院分区：
文献类型：
--
作者：
Ticozzi, N.;Ratti, A.;Silani, V.
中枢神经系统内蛋白质内含物的存在是大多数神经退行性疾病的特征，包括肌萎缩性侧索硬化症（ALS）。聚集体可以通过几种机制诱导细胞死亡，例如必需细胞组分的隔离、蛋白酶体系统的堵塞和/或轴突运输的破坏。ALS的神经病理学特征表现为运动神经元细胞质中存在对TDP-43蛋白免疫反应的泛素化包涵体。最近的研究表明，相当大比例的家族性ALS病例是由TAR DNA结合蛋白中的致病性突变引起的，并在肉瘤中融合/在脂肪肉瘤中易位，分别编码TDP-43和FUS蛋白。TDP-43和FUS都是DNA/RNA结合蛋白，参与转录调控和mRNA分子的剪接、穿梭、成熟和转运。这两个基因的突变似乎诱导FUS和TDP-43的核质再分布，可能促进聚集体形成和/或破坏它们的生理核功能或它们与特定RNA靶标的相互作用。这些发现共同表明，细胞RNA代谢的改变可能引发运动神经元变性。
The presence of protein inclusions within the central nervous system is a characteristic of most neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Aggregates may induce cell death trough several mechanisms, such as sequestration of essential cellular components, clogging of the proteasome system, and/or disruption of axonal transport. The neuropathological signature of ALS is represented by the presence of ubiquitinated inclusions immunoreactive for the protein TDP-43 in the cytoplasm of motor neurons. Recent studies demonstrated that a significant percentage of familial ALS cases are caused by pathogenic mutations in the TAR DNA binding protein and fused in sarcoma/translocated in liposarcoma genes encoding, respectively, for TDP-43 and FUS proteins. Both TDP-43 and FUS are DNA/RNA-binding proteins involved in transcriptional regulation and splicing, shuttling, maturation and transport of mRNA molecules. Mutations in the two genes seem to induce a nucleo-cytoplasmic redistribution of FUS and TDP-43, possibly promoting aggregate formation and/or disrupting their physiological nuclear functions or their interactions with specific RNA targets. Those findings collectively suggest that alterations in cellular RNA metabolism may trigger motor neuron degeneration.