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: 6.39). 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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    • "In response to arsenite-induced oxidative stress, TDP-43 depletion does not influence eIF2α phosphorylation (McDonald et al., 2011). However, SG dynamics are affected at several levels such that SG assembly is delayed, secondary aggregation is abrogated and disassembly is accelerated (McDonald et al., 2011). The SG proteins G3BP1 and TIA-1 are down and up-regulated, respectively, in cells depleted of TDP-43 (McDonald et al., 2011). "
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    ABSTRACT: Stress granules (SGs) are RNA-containing cytoplasmic foci formed in response to stress exposure. Since their discovery in 1999, over 120 proteins have been described to be localized to these structures (in 154 publications). Most of these components are RNA binding proteins (RBPs) or are involved in RNA metabolism and translation. SGs have been linked to several pathologies including inflammatory diseases, cancer, viral infection, and neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). In ALS and FTD, the majority of cases have no known etiology and exposure to external stress is frequently proposed as a contributor to either disease initiation or the rate of disease progression. Of note, both ALS and FTD are characterized by pathological inclusions, where some well-known SG markers localize with the ALS related proteins TDP-43 and FUS. We propose that TDP-43 and FUS serve as an interface between genetic susceptibility and environmental stress exposure in disease pathogenesis. Here, we will discuss the role of TDP-43 and FUS in SG dynamics and how disease-linked mutations affect this process.
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    • "In particular, recent studies have reported the binding of different members of the heterogeneous nuclear ribonucleoprotein family of RBPs to C9orf72 repeats, probably resulting in their redistribution from the nucleus to the cytosol (Mori et al., 2013; Sareen et al., 2013). These last findings thus highlight that abnormal RBPs redistribution in cellular inclusions might play a role in ALS pathology, and strengthen the participation of the heterogeneous nuclear ribonucleoprotein family to this more general phenomenon, firstly observed for the ALS related TDP-43 and FUS proteins and now also for other RBPs such as HuR and TiaR (Lu et al., 2009; McDonald et al., 2011). "
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    • "This mutation can impair binding to PPI/ CypA with respect to wild type. Johnson et al. (2009), Kim et al. (2010), Lauranzano et al. (2015), McDonald et al. (2011) p.R361T Chiang et al.(2012) n.d. p.P363A Daoud et al. (2009) n.d. "
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    ABSTRACT: At present, there are very few therapeutic options for patients affected by amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). However, almost all patients affected by ALS or tau-negative FTD share in their brains the presence of aggregated TDP-43, a nuclear factor that plays an important role in regulating RNA metabolism. For this reason, this protein represents a very promising target to develop novel therapeutic options. Over the years, these options have mostly involved the search for new effectors capable of reducing aberrant aggregation or enhancing its clearance by UPS-dependent protein quality control or autophagy system. Targeting eventual mutations in the sequence of this protein might represent a parallel alternative therapeutic option. To this date, the study of various patient populations has allowed to find more than 50 mutations associated with disease. It is, therefore, important to better understand what the functional consequences of these mutations are. As discussed in this review, the emerging picture is that most TDP-43 mutations appear to directly relate to specific disease features such as increased aggregation, half-life, or altered cellular localization and protein-protein interactions.
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