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TAR DNA-binding protein 43 (TDP-43) regulates stress granule dynamics via differential regulation of G3BP and TIA-1

Centre d'excellence en neuromique de l'Université de Montréal, Centre de recherche du CHUM, Montréal, QC, Canada.
Human Molecular Genetics (Impact Factor: 6.68). 03/2011; 20(7):1400-10. DOI: 10.1093/hmg/ddr021
Source: PubMed

ABSTRACT TAR deoxyribonucleic acid-binding protein 43 (TDP-43) is a multifunctional protein with roles in transcription, pre-messenger ribonucleic acid (mRNA) splicing, mRNA stability and transport. TDP-43 interacts with other heterogeneous nuclear ribonucleoproteins (hnRNPs), including hnRNP A2, via its C-terminus and several hnRNP family members are involved in the cellular stress response. This relationship led us to investigate the role of TDP-43 in cellular stress. Our results demonstrate that TDP-43 and hnRNP A2 are localized to stress granules (SGs), following oxidative stress, heat shock and exposure to thapsigargin. TDP-43 contributes to both the assembly and maintenance of SGs in response to oxidative stress and differentially regulates key SGs components, including TIA-1 and G3BP. The controlled aggregation of TIA-1 is disrupted in the absence of TDP-43 resulting in slowed SG formation. In addition, TDP-43 regulates the levels of G3BP mRNA, a SG nucleating factor. The disease-associated mutation TDP-43(R361S) is a loss-of-function mutation with regards to SG formation and confers alterations in levels of G3BP and TIA-1. In contrast, a second mutation TDP-43(D169G) does not impact this pathway. Thus, mutations in TDP-43 are mechanistically divergent. Finally, the cellular function of TDP-43 extends beyond splicing and places TDP-43 as a participant of the central cellular response to stress and an active player in RNA storage.

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Available from: Christine Vande Velde, May 26, 2015
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    • "However, under pathological conditions or due to chronic stress, these granules may act as precursors of the pathologic inclusions or pre-inclusions, which may transform into irreversible dense aggregates that can act as seeds of aggregation (Fig. 1B). Indeed, TDP-43 (Bentmann et al., 2012; Fujita et al., 2008; Liu-Yesucevitz et al., 2010; McDonald et al., 2011; Udan-Johns et al., 2014) and FUS (Bentmann et al., 2012; Dormann et al., 2010) are incorporated in cytoplasmic and nuclear RNA granules. Stress granules and other RNA granules are likely to act as sites of nucleation, due to the increase of local TDP-43 and FUS concentration, which could facilitate the initiation of their aggregation . "
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    • "In addition to cytoplasmic redistribution, we showed that the M337V mutation had a clear effect on increasing the number of cytoplasmic TDP-43 aggregates, even in the absence of external cellular stressors, while the A382T mutation required ER stress induction to elevate levels of cytoplasmic aggregates. Similar TDP-43 cytoplasmic aggregates have been previously reported and associated with stress granules (McDonald et al, 2011). Under basal and ER stress conditions , nuclear TDP-43 aggregates were detected more frequently in cells expressing the M337V and A382T mutations compared with cells expressing wt-TDP. "
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    • "The most comprehensive study on the functional role of TDP-43 in SGs and cellular stress response has been performed by McDonald et al. (2011) (75). These authors showed that TDP-43 and its binding partner hnRNP A2 are components of SGs formed in response to oxidative stress. "
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