Role of selected mutations in the Q/N rich region of TDP-43 in EGFP-12xQ/N-induced aggregate formation
- 作者：Mauricio Budini ; Valentina Romano ; S. Eré ; ndira Avendañ ; o-Vá ; zquez ; Sara Bembich ; Emanuele Buratti ; Francisco E. Baralle ; baralle@icgeb.org
- 关键词：TDP-43 ; Aggregation ; Q/N regions ; Polyglutamine ; Autoregulation ; Disease mutations ; Splicing
- 刊名：Brain Research
- 出版年：2012
- 期刊代码：8_00068993
- 类别：neu
- 出版时间：26 June, 2012
- 卷：1462
- 期：Complete
- 页码：139-150
- 文件大小：1687 K
摘要
The overview of TDP 43 functions immediately disclose a number of open questions regarding its pathological role. The formation of TDP-43 aggregates is one of the major distinguishing features of TDP-43 proteinopathies, especially in patients affected by Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Lobar degeneration (FTLD). At the moment, however, very little is known regarding the biological processes that underlie TDP-43 aggregation and, most importantly, its potential consequences on cellular metabolism. For these reasons, it is particularly important to further investigate this process in order to gain a better understanding of the pathology and to develop novel therapeutic effectors. In this report, we focus on a series of missense mutations associated with disease in the 342-366 region of this protein to examine their ability to affect RNA splicing regulation and to induce aggregate formation. In particular, aggregate formation was assessed in a novel system capable of inducing TDP-43 aggregation in experimental cell lines and primary neuronal cultures. The results of this analysis showed that the presence of two of these missense mutations in the 342-366 region (G348V and N352S) could differentially affect the levels and appearance of TDP-43 aggregation with respect to the wild-type protein.
This article is part of a Special Issue entitled RNA-Binding Proteins.