TDP-43 in central nervous system development and function: Clues to TDP-43-associated neurodegeneration

Deparment of Neuroscience, The University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390-9111, USA.
Biological Chemistry (Impact Factor: 3.27). 07/2012; 393(7):589-94. DOI: 10.1515/hsz-2012-0115
Source: PubMed


From the earliest stages of embryogenesis and throughout life, transcriptional regulation is carefully orchestrated in order to generate, shape, and reshape the central nervous system (CNS). TAR DNA-binding protein 43 (TDP-43) is identified as a regulator of essential transcriptional events in the CNS. Evidence for its importance comes from the identification of TDP-43 protein aggregates and genetic mutations in patients with amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Efforts are being made to learn more about the biological function of TDP-43 and gain a better understanding of its role in neurodegeneration. TDP-43 RNA targets and protein interactions have now been identified, and in vivo evidence shows that TDP-43 is essential in CNS development and function. This review will highlight aspects of these findings.

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Available from: Chantelle F Sephton
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    • "The pathogenesis of these TDP-43 proteinopathies is dependent on a variety of putative TDP-43 functions. Overall, it is now accepted that TDP-43 is a global regulator of transcription and tissue-specific gene expression and TDP-43 has an important role in the development of neurodegenerative disorders called TDP-43 proteinopathies [7], [9], [10] (for a recent review see also [11]). By its RNA recognition motif it is involved in multiple aspects of RNA metabolism, including transcription, splicing, RNA transport, RNA stability and turnover as well as microRNA biogenesis [12]–[14]. "
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    ABSTRACT: The TAR DNA binding protein (TDP-43) was originally identified as a host cell factor binding to the HIV-1 LTR and thereby suppressing HIV-1 transcription and gene expression (Ou et al., J.Virol. 1995, 69(6):3584). TDP-43 is a global regulator of transcription, can influence RNA metabolism in many different ways and is ubiquitously expressed. Thus, TDP-43 could be a major factor restricting HIV-1 replication at the level of LTR transcription and gene expression. These facts prompted us to revisit the role of TDP-43 for HIV-1 replication. We utilized established HIV-1 cell culture systems as well as primary cell models and performed a comprehensive analysis of TDP-43 function and investigated its putative impact on HIV-1 gene expression. In HIV-1 infected cells TDP-43 was neither degraded nor sequestered from the nucleus. Furthermore, TDP-43 overexpression as well as siRNA mediated knockdown did not affect HIV-1 gene expression and virus production in T cells and macrophages. In summary, our experiments argue against a restricting role of TDP-43 during HIV-1 replication in immune cells.
    Full-text · Article · Aug 2014 · PLoS ONE
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    • "TDP43 is a nuclear protein that plays crucial roles in gene expression and alternative splicing [25], [26], embryogenesis [27]–[30], the stress response [31]–[36], neuronal functions such as neurite outgrowth [37]–[39] and many other cellular processes [30], [40], [41]. It is currently unknown whether mutant TDP43 causes neuronal degeneration through loss of one of these functions or via a novel gain-of-function mechanism, or through both [1], [42], [43]. "
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    ABSTRACT: Mutations in TARDBP, encoding Tar DNA binding protein-43 (TDP43), cause amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Attempts to model TDP43 dysfunction in mice have used knockouts or transgenic overexpressors, which have revealed the difficulties of manipulating TDP43, whose level is tightly controlled by auto-regulation. In a complementary approach, to create useful mouse models for the dissection of TDP43 function and pathology, we have identified a nonsense mutation in the endogenous mouse Tardbp gene through screening an N-ethyl-N-nitrosourea (ENU) mutant mouse archive. The mutation is predicted to cause a Q101X truncation in TDP43. We have characterised Tardbp(Q101X) mice to investigate this mutation in perturbing TDP43 biology at endogenous expression levels. We found the Tardbp(Q101X) mutation is homozygous embryonic lethal, highlighting the importance of TDP43 in early development. Heterozygotes (Tardbp(+/Q101X) ) have abnormal levels of mutant transcript, but we find no evidence of the truncated protein and mice have similar full-length TDP43 protein levels as wildtype littermates. Nevertheless, Tardbp(+/Q101X) mice have abnormal alternative splicing of downstream gene targets, and limb-clasp and body tone phenotypes. Thus the nonsense mutation in Tardbp causes a mild loss-of-function phenotype and behavioural assessment suggests underlying neurological abnormalities. Due to the role of TDP43 in ALS, we investigated potential interactions with another known causative gene, mutant superoxide dismutase 1 (SOD1). Tardbp(+/Q101X) mice were crossed with the SOD1(G93Adl) transgenic mouse model of ALS. Behavioural and physiological assessment did not reveal modifying effects on the progression of ALS-like symptoms in the double mutant progeny from this cross. In summary, the Tardbp(Q101X) mutant mice are a useful tool for the dissection of TDP43 protein regulation, effects on splicing, embryonic development and neuromuscular phenotypes. These mice are freely available to the community.
    Full-text · Article · Jan 2014 · PLoS ONE
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    • "For example, the data point out to the potential involvement of TDP-43 in maintaining steady state levels of messenger molecules with particularly long introns. There are also indications for a role of TDP-43 in regulating long non-coding RNAs, or shared targets with other RBP proteins involved in neurodegeneration, as recently reviewed elsewhere (Gitler, 2012; Polymenidou et al., 2012; Sephton et al., 2012). "
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    ABSTRACT: Dysfunctions in RNA processing and in particular the aberrant regulation of RNA binding proteins (RBPs) have recently been shown to play a fundamental role in the pathogenesis of neurodegenerative diseases. Understanding the pathogenic mechanisms involved will require the elucidation of the role(s) played by these RBPs in the general cell metabolism and neuronal survival in particular. In the past, the preferred approach has been to determine first of all the functional properties of the factor(s) of interest and then use of this knowledge to determine targets in biologically relevant events. More recently, novel experimental approaches such as microarrays, RNA-seq and CLIP-seq have also become very popular to study RBPs. The advantage of these approaches, collectively known as High Throughput Screening (HTS), is their ability to determine gene expression changes or RNA/protein targets at a global cellular level. In theory, HTS strategies should be ideal for uncovering novel functional roles/targets of any RBP inside the cell. In practice, however, there are still difficulties in getting a coherent picture from all the huge amount of data they generate, frequently not validated experimentally and thus of unknown value. They may even act unfavorably towards a specific increase of knowledge of RBP functions, as the incomplete results are taken as solid data. In this work we will illustrate as an example the use of the HTS methodologies to characterize the interactions of a specific RNA binding protein: TDP-43. The multiple functions of this protein in RNA processing and its involvement in the pathogenesis of several forms of ALS, FTLD and other neurodegenerative diseases make it an excellent substrate for our analysis of the various advantages and limitations of different HTS experimental approaches.
    Full-text · Article · Mar 2013 · Molecular and Cellular Neuroscience
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