Cellular Model of TAR DNA-binding Protein 43 (TDP-43) Aggregation Based on Its C-terminal Gln/Asn-rich Region
Cellular Model of TAR DNA-binding Protein 43 (TDP-43) Aggregation Based on Its C-terminal Gln/Asn-rich Region
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DOI：
10.1074/jbc.m111.288720
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发表时间：
2012-03-02
影响因子：
4.8
通讯作者：
Baralle, Francisco E.
中科院分区：
文献类型：
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作者：
Budini, Mauricio;Buratti, Emanuele;Baralle, Francisco E.
TDP-43是在几种神经退行性疾病如肌萎缩侧索硬化和额颞叶变性中观察到的神经元和神经胶质包涵体的主要组分之一。这些特征性聚集体是疾病的“里程碑”，但它们在发病机制中的作用仍然不清楚。在以前的工作中，我们已经表明，TDP-43的C-末端Gln/Asnrich区域（残基321-366）参与这种蛋白质与异质核核糖核蛋白家族的其他成员的相互作用。此外，我们已经表明，通过该区域的相互作用是重要的TDP-43剪接抑制囊性纤维化跨膜调节因子外显子9，有迹象表明，它参与了聚集过程。我们的实验表明，在细胞系和原代大鼠神经元培养物中，引入携带TDP-43的331-369-残基Gln/Asn区域的串联重复序列可以触发磷酸化和泛素化聚集体的形成，这些聚集体概括了许多但不是所有在患者中观察到的特征。这些结果建立了一个非常需要的基于细胞的TDP-43聚集模型，可用于研究包涵体形成的机制和TDP-43聚集在细胞内的功能获得和丧失的后果。此外，它将成为测试旨在预防/减少这种现象的新型治疗策略/效应器的有力工具。
TDP-43 is one of the major components of the neuronal and glial inclusions observed in several neurodegenerative diseases such as amyotrophic lateral sclerosis and frontotemporal lobar degeneration. These characteristic aggregates are a "landmark" of the disease, but their role in the pathogenesis is still obscure. In previous works, we have shown that the C-terminal Gln/Asnrich region (residues 321-366) of TDP-43 is involved in the interaction of this protein with other members of the heterogeneous nuclear ribonucleoprotein protein family. Furthermore, we have shown that the interaction through this region is important for TDP-43 splicing inhibition of cystic fibrosis transmembrane regulator exon 9, and there were indications that it was involved in the aggregation process. Our experiments show that in cell lines and primary rat neuronal cultures, the introduction of tandem repeats carrying the 331-369-residue Gln/Asn region from TDP-43 can trigger the formation of phosphorylated and ubiquitinated aggregates that recapitulate many but not all the characteristics observed in patients. These results establish a much needed cell-based TDP-43 aggregation model useful to investigate the mechanisms involved in the formation of inclusions and the gain-and loss-of-function consequences of TDP-43 aggregation within cells. In addition, it will be a powerful tool to test novel therapeutic strategies/effectors aimed at preventing/reducing this phenomenon.