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

Article (PDF Available)inHuman Molecular Genetics 20(7):1400-10 · March 2011with53 Reads
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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    • "Mutations disrupt cytoplasmic SGs that contain translationally silenced RNA transported to target sites, enabling the cell to carry out protein synthesis. TDP-43 mutants may also be incorporated in the early stage of SG formation, resulting in larger and deregulated granules (Dewey et al., 2011; McDonald et al., 2011). The pathogenic mechanisms of TARDBP mutations are still unclear; mutations most likely affect normal functions of TDP-43 by gain-of-toxicity or loss-of-function, mediated by enhanced aggregation and nuclear depletion. "
    [Show abstract] [Hide abstract] ABSTRACT: Amyotrophic lateral sclerosis (ALS), a common motor neuron disease affecting two per 100,000 people worldwide, encompasses at least five distinct pathological subtypes, including, ALS-SOD1, ALS-C9orf72, ALS-TDP-43, ALS-FUS and Guam-ALS. The etiology of a major subset of ALS involves toxicity of the TAR DNA-binding protein-43 (TDP-43). A second RNA/DNA binding protein, fused in sarcoma/translocated in liposarcoma (FUS/TLS) has been subsequently associated with about 1% of ALS patients. While mutations in TDP-43 and FUS have been linked to ALS, the key contributing molecular mechanism(s) leading to cell death are still unclear. One unique feature of TDP-43 and FUS pathogenesis in ALS is their nuclear clearance and simultaneous cytoplasmic aggregation in affected motor neurons. Since the discoveries in the last decade implicating TDP-43 and FUS toxicity in ALS, a majority of studies have focused on their cytoplasmic aggregation and disruption of their RNA-binding functions. However, TDP-43 and FUS also bind to DNA, although the significance of their DNA binding in disease-affected neurons has been less investigated. A recent observation of accumulated genomic damage in TDP-43 and FUS-linked ALS and association of FUS with neuronal DNA damage repair pathways indicate a possible role of deregulated DNA binding function of TDP-43 and FUS in ALS. In this review, we discuss the different ALS disease subtypes, crosstalk of etiopathologies in disease progression, available animal models and their limitations, and recent advances in understanding the specific involvement of RNA/DNA binding proteins, TDP-43 and FUS, in motor neuron diseases.
    Full-text · Article · Sep 2016 · Cell Reports
    • "Interestingly, both TDP-43 and FUS were found to colocalize with stress granule proteins, including TIA-1 (Fujita et al. 2008; Liu-Yesucevitz et al. 2010), PABP-1 (Bentmann et al. 2012), and eIF3 (Liu-Yesucevitz et al. 2010) in ALS and FTD patients. Several stressors, such as oxidative, osmotic, heat shock, and ER stress were able to recapitulate the cytoplasmic redistribution and stress granule association of TDP-43 (Colombrita et al. 2009; Liu-Yesucevitz et al. 2010; Dewey et al. 2011; McDonald et al. 2011; Leggett et al. 2012 ). Importantly, some of these stressinduced granules turned into insoluble aggregates and were shown to persist after removal of the stressor (Dewey et al. 2011; Cohen et al. 2015; Feiler et al. 2015; Kabuta et al. 2015). "
    [Show abstract] [Hide abstract] ABSTRACT: Frontotemporal dementia is a devastating neurodegenerative disease causing stark alterations in personality and language. Characterized by severe atrophy of the frontal and temporal brain lobes, frontotemporal dementia (FTD) shows extreme heterogeneity in clinical presentation, genetic causes, and pathological findings. Like most neurodegenerative diseases, the initial symptoms of FTD are subtle, but increase in severity over time, as the disease progresses. Clinical progression is paralleled by exacerbation of pathological findings and the involvement of broader brain regions, which currently lack mechanistic explanation. Yet, a flurry of studies indicate that protein aggregates accumulating in neurodegenerative diseases can act as propagating entities, amplifying their pathogenic conformation, in a way similar to infectious prions. In this prion-centric view, FTD can be divided into three subtypes, TDP-43 or FUS proteinopathy and tauopathy. Here, we review the current evidence that FTD-linked pathology propagates in a prion-like manner and discuss the implications of these findings for disease progression and heterogeneity. Frontotemporal dementia (FTD) is a progressive neurodegenerative disease causing severe personality dysfunctions, characterized by profound heterogeneity. Accumulation of tau, TDP-43 or FUS cytoplasmic aggregates characterize molecularly distinct and non-overlapping FTD subtypes. Here, we discuss the current evidence suggesting that prion-like propagation and cell-to-cell spread of each of these cytoplasmic aggregates may underlie disease progression and heterogeneity. This article is part of the Frontotemporal Dementia special issue.
    Full-text · Article · Aug 2016
    • "Intriguingly, a recent in vitro study showed that TDP43 can autonomously phaseseparate (Molliex et al., 2015). Motivated by these findings and the known association of TDP43 with MLOs such as stress and transport granules (Alami et al., 2014; Colombrita et al., 2009; McDonald et al., 2011), we explored the hypothesis that TDP43 may form liquid-like phases in cells and that ALS-linked mutations can alter the phase properties. We find that TDP43 has the potential to form micron-sized liquid droplets containing internal, nucleoplasm-filled ''bubbles.'' "
    [Show abstract] [Hide abstract] ABSTRACT: Eukaryotic cells contain membrane-less organelles, including nucleoli and stress granules, that behave like liquid droplets. Such endogenous condensates often have internal substructure, but how this is established in the absence of membrane encapsulation remains unclear. We find that the N- and C-terminal domains of TDP43, a heterogeneous nuclear ribonucleoprotein implicated in neurodegenerative diseases, are capable of driving the formation of sub-structured liquid droplets in vivo. These droplets contain dynamic internal “bubbles” of nucleoplasm, reminiscent of membrane-based multi-vesicular endosomes. A conserved sequence embedded within the intrinsically disordered region (IDR) of TDP43 promotes the formation of these multi-phase assemblies. Disease-causing point mutations in the IDR can change the propensity to form bubbles, protein dynamics within the phase, or phase-environment exchange rates. Our results show that a single IDR-containing protein can nucleate the assembly of compartmentalized liquid droplets approximating the morphological complexity of membrane-bound organelles.
    Full-text · Article · Jul 2016
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