TAR-DNA-binding protein 43 (TDP-43), encoded by the TARDBP gene on chromosome 1p36.22, has been identified as the major pathological protein in abnormal inclusions in neurons and glial cells in sporadic amyotrophic lateral sclerosis (SALS), SOD1-negative familial ALS (FALS) and frontotemporal lobar dementia (FTLD). Twenty mutations of TARDBP in SOD1-negative FALS and SALS cases have been reported so far. To investigate the presence and frequency of TARDBP mutations in Japanese SOD1-negative FALS patients, we performed mutational screening of TARDBP in 30 SOD1-negative FALS patients. An N352S mutation was found in one case of FALS, but no TARDBP mutations were found in cases of SALS. It was thought that this mutation increases TDP-43 phosphorylation. This might lead to impaired nuclear cytoplasmic transport or protein-protein interaction, thereby leading to TDP-43 accumulation.
"G348R (Ticozzi et al., 2011b) One FALS patient carrying this mutation also carried a missense mutation, R395Q in the TAF15 gene. N352S (Iida et al., 2010; Kamada et al., 2009; Kuhnlein et al., 2008) n.d. N352T (Ticozzi et al., 2011a) n.d. "
[Show abstract][Hide abstract] ABSTRACT: The overview of TDP 43 functions immediately disclose a number of open questions regarding its pathological role. The formation of TDP-43 aggregates is one of the major distinguishing features of TDP-43 proteinopathies, especially in patients affected by Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Lobar degeneration (FTLD). At the moment, however, very little is known regarding the biological processes that underlie TDP-43 aggregation and, most importantly, its potential consequences on cellular metabolism. For these reasons, it is particularly important to further investigate this process in order to gain a better understanding of the pathology and to develop novel therapeutic effectors. In this report, we focus on a series of missense mutations associated with disease in the 342-366 region of this protein to examine their ability to affect RNA splicing regulation and to induce aggregate formation. In particular, aggregate formation was assessed in a novel system capable of inducing TDP-43 aggregation in experimental cell lines and primary neuronal cultures. The results of this analysis showed that the presence of two of these missense mutations in the 342-366 region (G348V and N352S) could differentially affect the levels and appearance of TDP-43 aggregation with respect to the wild-type protein. This article is part of a Special Issue entitled RNA-Binding Proteins.
Brain research 02/2012; 1462:139-50. DOI:10.1016/j.brainres.2012.02.031 · 2.84 Impact Factor
"The Gly40Gly which has not been reported previously was found in one SALS patient and none of 200 unrelated control individuals, indicating that it is a rare silent mutation. The Ala366Ala which has been previously reported in Japanese SALS patients  was found in one SALS patient and one control individual, thus it was thought to be a benign polymorphism. We also have detected a novel polymorphism 239-18t>c in one SALS patient and one control individual. "
[Show abstract][Hide abstract] ABSTRACT: TARDBP mutations have been reported in patients with amyotrophic lateral sclerosis (ALS) in different populations except Chinese. The present aim is to investigate the association between TARDBP mutations and Chinese patients with ALS.
71 SALS patients and 5 FALS families with non-SOD1 mutations were screened for TARDBP mutations via direct sequencing.
A novel heterozygous variation, Ser292Asn (875G>A), was identified in the proband and 4 asymptomatic relatives including the children of the dead patient from a FALS family. Thus the dead patient, the proband's brother, was speculated to carry Ser292Asn though his sample was unavailable to the detection. This variation was not found in 200 unrelated control subjects. A homology search of the TDP-43 protein in different species demonstrated that it was highly conserved. Also, it was predicted to be deleterious to protein function with SIFT-calculated probabilities of 0.00. Therefore, Ser292Asn is predicted to be a pathogenic mutation. In addition, we have found two silent mutations (Gly40Gly and Ala366Ala) and one novel polymorphism (239-18t>c).
The present data have extended the spectrum of TARDBP mutations and polymorphisms, and supported the pathological role of TDP-43 in Chinese ALS patients.
BMC Medical Genetics 01/2010; 11(1):8. DOI:10.1186/1471-2350-11-8 · 2.08 Impact Factor
"The relevance of TDP-43 and its pathological variants was strongly supported by the discovery of a number of autosomal dominant mutations within the TDP-43 encoding gene (Rademakers and Hutton 2007; Gitcho et al. 2008; Kabashi et al. 2008; Kuhnlein et al. 2008; Rutherford et al. 2008; Sreedharan et al. 2008; Van Deerlin et al. 2008; Yokoseki et al. 2008; Benajiba et al. 2009; Corrado et al. 2009; Daoud et al. 2009; Del Bo et al. 2009; Kamada et al. 2009; Lemmens et al. 2009). So far, most of the point mutations are located within the C-terminal portion of TDP- 43, further supporting the pivotal function of the CTFs for disease onset and progression. "
[Show abstract][Hide abstract] ABSTRACT: Neuronal and glial deposition of misfolded, proteolytically processed, polyubiquitinated and abnormally phosphorylated C-terminal fragments (CTFs) of the TAR DNA binding protein-43 (TDP-43) is a pathological hallmark of frontotemporal lobar degeneration with ubiquitin positive inclusions (FTLD-U) and certain cases of amyotrophic lateral sclerosis. We demonstrate that TDP-43 can be proteolytically processed by caspases upon induction of apoptosis to a major 35 kDa and a minor 25 kDa CTF. These fragments are initially soluble, but over time they accumulate as insoluble and pathologically phosphorylated derivatives. However, proteolytic processing appears not to be absolutely required for the deposition of insoluble TDP-43 species, since a caspase resistant mutant of TDP-43 is also converted into insoluble species. Phosphorylation at S409/410 apparently occurs late during the conversion of soluble to insoluble TDP-43, suggesting that phosphorylation is not a prerequisite for aggregation. Loss of function of the progranulin (PGRN) gene causes FTLD-U with TDP-43 positive inclusions and has been suggested to lead to caspase activation and subsequent TDP-43 processing. However, siRNA-mediated knockdown of PGRN in cell culture as well as a PGRN gene knockout in mice failed to cause the formation of the disease characterizing CTFs of TDP-43. Our findings therefore suggest that caspase-mediated processing generates CTFs of similar biochemical properties as those occurring in nuclear and cytoplasmic deposits of FTLD-U patients independent of PGRN levels.
Journal of Neurochemistry 07/2009; 110(3):1082-94. DOI:10.1111/j.1471-4159.2009.06211.x · 4.28 Impact Factor
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