TARDBP mutations in amyotrophic lateral sclerosis with TDP-43 neuropathology: a genetic and histopathological analysis. Lancet Neurol 7:409-416
ABSTRACT TDP-43 is a major component of the ubiquitinated inclusions that characterise amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) with ubiquitin inclusions (FTLD-U). TDP-43 is an RNA-binding and DNA-binding protein that has many functions and is encoded by the TAR DNA-binding protein gene (TARDBP) on chromosome 1. Our aim was to investigate whether TARDBP is a candidate disease gene for familial ALS that is not associated with mutations in superoxide dismutase 1 (SOD1).
TARDBP was sequenced in 259 patients with ALS, FTLD, or both. We used TaqMan-based SNP genotyping to screen for the identified variants in control groups matched to two kindreds of patients for age and ethnic origin. Additional clinical, genetic, and pathological assessments were made in these two families.
We identified two variants in TARDBP, which would encode Gly290Ala and Gly298Ser forms of TDP-43, in two kindreds with familial ALS. The variants seem to be pathogenic because they co-segregated with disease in both families, were absent in controls, and were associated with TDP-43 neuropathology in both members of one of these families for whom CNS tissue was available.
The Gly290Ala and Gly298Ser mutations are located in the glycine-rich domain of TDP-43, which regulates gene expression and mediates protein-protein interactions such as those with heterogeneous ribonucleoproteins. Owing to the varied and important cellular functions of TDP-43, these mutations might cause neurodegeneration through both gains and losses of function. The finding of pathogenic mutations in TARDBP implicates TDP-43 as an active mediator of neurodegeneration in TDP-43 proteinopathies, a class of disorder that includes ALS and FTLD-U.
National Institutes of Health (AG10124, AG17586, AG005136-22, PO1 AG14382), Department of Veterans Affairs, Friedrich-Baur Stiftung (0017/2007), US Public Health Service, ALS Association, and Fundació 'la Caixa'.
- SourceAvailable from: Kavitha Siva
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- "Findings that showed the presence of ubiquitinated protein TDP-43 in sporadic cases of ALS with FTD further linked these two diseases (Arai et al., 2006; Neumann et al., 2006). Following these findings, mutations in the gene coding for the RNA binding protein TDP-43 were discovered in ALS cases (Kabashi et al., 2008; Sreedharan et al., 2008; Van Deerlin et al., 2008) and FTD cases (Borroni et al., 2009; Kovacs et al., 2009). With the broadening knowledge on the impact of impaired RNA binding proteins in mediating the disease process, mutations in the fused in sarcoma/translocated in liposarcoma (FUS/TLS) gene were found to account for an additional 5% of familial ALS and few rare cases of FTD (Kwiatkowski et al., 2009; Vance et al., 2009). "
ABSTRACT: Frontotemporal dementia (FTD) is a neurodegenerative disorder characterized by degeneration of the fronto temporal lobes and abnormal protein inclusions. It exhibits a broad clinicopathological spectrum and has been linked to mutations in seven different genes. We will provide a picture, which connects the products of these genes, albeit diverse in nature and function, in a network. Despite the paucity of information available for some of these genes, we believe that RNA processing and post-transcriptional regulation of gene expression might constitute a common theme in the network. Recent studies have unraveled the role of mutations affecting the functions of RNA binding proteins and regulation of microRNAs. This review will combine all the recent findings on genes involved in the pathogenesis of FTD, highlighting the importance of a common network of interactions in order to study and decipher the heterogeneous clinical manifestations associated with FTD. This approach could be helpful for the research of potential therapeutic strategies.Frontiers in Molecular Neuroscience 03/2015; 8:9. DOI:10.3389/fnmol.2015.00009 · 4.08 Impact Factor
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- "While in healthy cells, TDP-43 localizes predominantly to the nucleus, in affected neurons and glial cells, it mislocalizes to the cytoplasm, where it forms pathogenic inclusions (Fig. 2B). This protein redistribution and cytoplasmic aggregation prevents TDP-43 from returning to the nucleus, leading to its nuclear clearing (Arai et al., 2006; Igaz et al., 2008; Neumann et al., 2006; Van Deerlin et al., 2008). Moreover, disease-associated TDP-43 presents a certain biochemical signature characterized by polyubiquitination, hyperphosphorylation and proteolytic cleavage (Arai et al., 2006; Neumann et al., 2006). "
ABSTRACT: Propagation of pathological protein assemblies via a prion-like mechanism has been suggested to drive neurodegenerative diseases, such as Parkinson's and Alzheimer's. Recently, amyotrophic lateral sclerosis (ALS)-linked proteins, such as SOD1, TDP-43 and FUS were shown to follow self-perpetuating seeded aggregation, thereby adding ALS to the group of prion-like disorders. The cell-to-cell spread of these pathological protein assemblies and their pathogenic mechanism is poorly understood. However, as ALS is a non-cell autonomous disease and pathology in glial cells was shown to contribute to motor neuron damage, spreading mechanisms are likely to underlie disease progression via the interplay between affected neurons and their neighboring glial cells.Virus Research 02/2015; 8. DOI:10.1016/j.virusres.2014.12.032 · 2.83 Impact Factor
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- "Deletion of TARDBP leads to embryonic lethality and in neuronal cultures loss of TDP-43 induces pre-mRNA missplicing and neuronal dysfunction (Daoud et al, 2009; Kabashi et al, 2008; Kraemer et al, 2010; Wu et al, 2010). Approximately 30 different mutations have been identified in TARDBP, accounting for approximately 4% of fALS patients and a small minority of cases of sALS, suggesting that it has a direct role in the pathogenesis of ALS (Daoud et al, 2009; Gitcho et al, 2008; Sreedharan et al, 2008; Van Deerlin et al, 2008; Yokoseki et al, 2008). The majority of mutations are concentrated in the C-terminal glycine-rich domain of TDP-43 and are predicted to result in abnormal RNA–protein or protein–protein interactions (Pesiridis et al, 2009). "
ABSTRACT: The transactive response DNA binding protein (TDP-43) is a major component of the characteristic neuronal cytoplasmic inclusions seen in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Furthermore, pathogenic mutations in the gene encoding TDP-43, TARDBP, are found in sporadic and familial ALS cases. To study the molecular mechanisms of cellular toxicity due to TDP-43 mutations we generated a novel in vitro cellular model using a fluorescently tagged human genomic TARDBP locus carrying one of two ALS-associated mutations, A382T or M337V, which were used to generate site-specific bacterial artificial chromosome (BAC) human stable cell lines and BAC transgenic mice. In cell lines and primary motor neurons in culture, TDP-M337V mislocalized to the cytoplasm more frequently than wild-type TDP (wt-TDP) and TDP-A382T, an effect potentiated by oxidative stress. Expression of mutant TDP-M337V correlated with increased apoptosis detected by cleaved caspase-3 staining. Cells expressing mislocalized TDP-M337V spontaneously developed cytoplasmic aggregates, while for TDP-A382T aggregates were only revealed after endoplasmic reticulum (ER) stress induced by the calcium-modifying drug thapsigargin. Lowering Ca(2+) concentration in the ER of wt-TDP cells partially recapitulated the effect of pathogenic mutations by increasing TDP-43 cytoplasmic mislocalization, suggesting Ca(2+) dysregulation as a potential mediator of pathology through alterations in Bcl-2 protein levels. Ca(2+) signalling from the ER was impaired in immortalized cells and primary neurons carrying TDP-43 mutations, with a 50% reduction in the levels of luminal ER Ca(2+) stores content and delayed Ca(2+) release compared to cells carrying wt-TDP. The deficits in Ca(2+) release in human cells correlated with upregulation of Bcl-2 and siRNA-mediated knockdown of Bcl-2 restored the amplitude of Ca(2+) oscillations in TDP-M337V cells. These results suggest that TDP-43 pathogenic mutations elicit cytoplasmic mislocalization of TDP-43 and Bcl-2 mediated ER Ca(2+) signaling dysregulation. Copyright © 2014. Published by Elsevier Inc.Neurobiology of Disease 12/2014; 75. DOI:10.1016/j.nbd.2014.12.010 · 5.20 Impact Factor