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Journal ArticleDOI

TARDBP mutations in individuals with sporadic and familial amyotrophic lateral sclerosis

TL;DR: Findings further corroborate that TDP-43 is involved in ALS pathogenesis and reports eight missense mutations in nine individuals—six from individuals with sporadic ALS and three from those with familial ALS (FALS)—and a concurring increase of a smaller T DP-43 product.
Abstract: Recently, TDP-43 was identified as a key component of ubiquitinated aggregates in amyotrophic lateral sclerosis (ALS), an adult-onset neurological disorder that leads to the degeneration of motor neurons. Here we report eight missense mutations in nine individuals--six from individuals with sporadic ALS (SALS) and three from those with familial ALS (FALS)--and a concurring increase of a smaller TDP-43 product. These findings further corroborate that TDP-43 is involved in ALS pathogenesis.
Citations
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Journal ArticleDOI
20 Oct 2011-Neuron
TL;DR: It is found that repeat expansion in C9ORF72 is a major cause of both FTD and ALS, suggesting multiple disease mechanisms.

4,153 citations


Cites background from "TARDBP mutations in individuals wit..."

  • ...For these reasons, the recent identification of mutations in TDP-43 (encoded by TARDBP) (Kabashi et al., 2008; Sreedharan et al., 2008) and the related RNA-binding protein fused in sarcoma (FUS) (Kwiatkowski et al., 2009; Vance et al., 2009) in 5% of familial ALS patients has significantly shifted…...

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  • ...MC Clinical FTD Familial 171 20 (11.7) 13 (7.6) 12 (6.3) n/a n/a n/a Sporadic 203 6 (3.0) 6 (3.0) 3 (1.5) n/a n/a n/a MCF Clinical ALS Familial 34 8 (23.5) n/a n/a 4 (11.8) 1 (2.9) 1 (2.9) Sporadic 195 8 (4.1) n/a n/a 0 (0.0) 2 (1.0) 3 (1.5) ALS = amyotrophic lateral sclerosis; c9FTD/ALS = (GGGGCC)n repeat expansion at chromosome 9p identified in this study; FTD = frontotemporal dementia; FTLD-TDP = frontotemporal lobar degeneration with TDP-43 pathology; FUS = fused in sarcoma gene; GRN = progranulin gene; MAPT =microtubule-associated protein tau gene; MC =Mayo Clinic; MCF =Mayo Clinic Florida; n/a = not assessed; SOD1 = superoxide dismutase 1 gene; TARDBP = TAR DNA-binding protein 43 gene; UBC = University of British Columbia. a Includes 22 individuals for which no information on family history was available. unrelated expanded repeat carriers had at least one copy of the ‘‘risk’’ haplotype (100...

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  • ...Importantly, a direct comparison of the frequency of repeat expansions in C9ORF72 with mutations in SOD1, TARDBP, and FUS revealed GGGGCC expansions to be the most common genetic cause of sporadic and familial ALS in our clinical series (Table 1)....

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  • ...For these reasons, the recent identification of mutations in TDP-43 (encoded by TARDBP) (Kabashi et al., 2008; Sreedharan et al., 2008) and the related RNA-binding protein fused in sarcoma (FUS) (Kwiatkowski et al., 2009; Vance et al., 2009) in 5% of familial ALS patients has significantly shifted the focus of ALS research and implicated abnormal RNA processing as a critical process in ALS pathogenesis (Lagier-Tourenne et al., 2010)....

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  • ...This familial association is not well explained by the currently recognized genetic defects; GRNmutations are not associated with significant motor neuron deficits, while patients carrying mutations in SOD1, TARDBP, or FUS are rarely affected by FTD. Linkage analysis in several autosomal-dominant families in which affected members develop either ALS or FTD or both, and where the pathology is consistently TDP positive, have suggested a major locus for FTD/ALS on chromosome 9p21....

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Journal ArticleDOI
27 Feb 2009-Science
TL;DR: Neuronal cytoplasmic protein aggregation and defective RNA metabolism thus appear to be common pathogenic mechanisms involved in ALS and possibly in other neurodegenerative disorders.
Abstract: Amyotrophic lateral sclerosis (ALS) is a fatal degenerative motor neuron disorder Ten percent of cases are inherited; most involve unidentified genes We report here 13 mutations in the fused in sarcoma/translated in liposarcoma (FUS/TLS) gene on chromosome 16 that were specific for familial ALS The FUS/TLS protein binds to RNA, functions in diverse processes, and is normally located predominantly in the nucleus In contrast, the mutant forms of FUS/TLS accumulated in the cytoplasm of neurons, a pathology that is similar to that of the gene TAR DNA-binding protein 43 (TDP43), whose mutations also cause ALS Neuronal cytoplasmic protein aggregation and defective RNA metabolism thus appear to be common pathogenic mechanisms involved in ALS and possibly in other neurodegenerative disorders

2,387 citations

Journal ArticleDOI
27 Feb 2009-Science
TL;DR: A missense mutation in the gene encoding fused in sarcoma (FUS) in a British kindred, linked to ALS6, is identified, which suggests that a common mechanism may underlie motor neuron degeneration.
Abstract: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that is familial in 10% of cases. We have identified a missense mutation in the gene encoding fused in sarcoma (FUS) in a British kindred, linked to ALS6. In a survey of 197 familial ALS index cases, we identified two further missense mutations in eight families. Postmortem analysis of three cases with FUS mutations showed FUS-immunoreactive cytoplasmic inclusions and predominantly lower motor neuron degeneration. Cellular expression studies revealed aberrant localization of mutant FUS protein. FUS is involved in the regulation of transcription and RNA splicing and transport, and it has functional homology to another ALS gene, TARDBP, which suggests that a common mechanism may underlie motor neuron degeneration.

2,373 citations

Journal ArticleDOI
10 Nov 2016-Nature
TL;DR: Extraordinary progress in understanding the biology of ALS provides new reasons for optimism that meaningful therapies will be identified, and emerging themes include dysfunction in RNA metabolism and protein homeostasis, with specific defects in nucleocytoplasmic trafficking.
Abstract: Amyotrophic lateral sclerosis (ALS) is a progressive and uniformly fatal neurodegenerative disease. A plethora of genetic factors have been identified that drive the degeneration of motor neurons in ALS, increase susceptibility to the disease or influence the rate of its progression. Emerging themes include dysfunction in RNA metabolism and protein homeostasis, with specific defects in nucleocytoplasmic trafficking, the induction of stress at the endoplasmic reticulum and impaired dynamics of ribonucleoprotein bodies such as RNA granules that assemble through liquid-liquid phase separation. Extraordinary progress in understanding the biology of ALS provides new reasons for optimism that meaningful therapies will be identified.

1,382 citations

Journal ArticleDOI
07 Aug 2013-Neuron
TL;DR: It is presented the case here that these two processes are intimately linked, with disease-initiated perturbation of either leading to further deviation of both protein and RNA homeostasis through a feedforward loop including cell-to-cell prion-like spread that may represent the mechanism for relentless disease progression.

1,347 citations

References
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Journal ArticleDOI
06 Oct 2006-Science
TL;DR: It is shown that TDP-43 is the major disease protein in both frontotemporal lobar degeneration with ubiquitin-positive inclusions and amyotrophic lateral sclerosis.
Abstract: Ubiquitin-positive, tau- and alpha-synuclein-negative inclusions are hallmarks of frontotemporal lobar degeneration with ubiquitin-positive inclusions and amyotrophic lateral sclerosis. Although the identity of the ubiquitinated protein specific to either disorder was unknown, we showed that TDP-43 is the major disease protein in both disorders. Pathologic TDP-43 was hyper-phosphorylated, ubiquitinated, and cleaved to generate C-terminal fragments and was recovered only from affected central nervous system regions, including hippocampus, neocortex, and spinal cord. TDP-43 represents the common pathologic substrate linking these neurodegenerative disorders.

5,440 citations

Journal ArticleDOI
TL;DR: The common occurrence of intracellular accumulations of TDP-43 supports the hypothesis that these disorders represent a clinicopathological entity of a single disease, and suggests that they can be newly classified as a proteinopathy of T DP-43.

2,263 citations

Journal ArticleDOI
TL;DR: This study investigated TDP‐43 in a larger series of ALS cases, including familial cases with and without SOD1 mutations, and identified it as the major pathological protein in sporadic ALS.
Abstract: Objective Amyotrophic lateral sclerosis (ALS) is a common, fatal motor neuron disorder with no effective treatment. Approximately 10% of cases are familial ALS (FALS), and the most common genetic abnormality is superoxide dismutase-1 (SOD1) mutations. Most ALS research in the past decade has focused on the neurotoxicity of mutant SOD1, and this knowledge has directed therapeutic strategies. We recently identified TDP-43 as the major pathological protein in sporadic ALS. In this study, we investigated TDP-43 in a larger series of ALS cases (n = 111), including familial cases with and without SOD1 mutations. Methods Ubiquitin and TDP-43 immunohistochemistry was performed on postmortem tissue from sporadic ALS (n = 59), ALS with SOD1 mutations (n = 15), SOD-1–negative FALS (n = 11), and ALS with dementia (n = 26). Biochemical analysis was performed on representative cases from each group. Results All cases of sporadic ALS, ALS with dementia, and SOD1-negative FALS had neuronal and glial inclusions that were immunoreactive for both ubiquitin and TDP-43. Cases with SOD1 mutations had ubiquitin-positive neuronal inclusions; however, no cases were immunoreactive for TDP-43. Biochemical analysis of postmortem tissue from sporadic ALS and SOD1-negative FALS demonstrated pathological forms of TDP-43 that were absent in cases with SOD1 mutations. Interpretation These findings implicate pathological TDP-43 in the pathogenesis of sporadic ALS. In contrast, the absence of pathological TDP-43 in cases with SOD1 mutations implies that motor neuron degeneration in these cases may result from a different mechanism, and that cases with SOD1 mutations may not be the familial counterpart of sporadic ALS. Ann Neurol 2007;61:427–434

906 citations

Journal ArticleDOI
TL;DR: This study aimed to determine the frequency of frontotemporal lobar degeneration with ubiquitinated inclusions (FTLD‐U) in the setting of hippocampal sclerosis and Alzheimer's disease using immunohistochemistry for TAR DNA binding protein 43 (TDP‐43), a putative marker for FTLD‐ U.
Abstract: Objective This study aimed to determine the frequency of frontotemporal lobar degeneration with ubiquitinated inclusions (FTLD-U) in the setting of hippocampal sclerosis (HpScl) and Alzheimer's disease (AD) using immunohistochemistry for TAR DNA binding protein 43 (TDP-43), a putative marker for FTLD-U. Methods Initially, 21 cases of HpScl associated with a variety of other pathological processes and 74 cases of AD were screened for FTLD-U with TDP-43 immunohistochemistry. A confirmation study was performed on 93 additional AD cases. Specificity of TDP-43 antibodies was assessed using double-immunolabeling confocal microscopy, immunoelectron microscopy, and biochemistry. Results TDP-43 immunoreactivity was detected in 71% of HpScl and 23% of AD cases. Double immunostaining of AD cases for TDP-43 and phospho-tau showed that the TDP-43–immunoreactive inclusions were usually distinct from neurofibrillary tangles. At the ultrastructural level, TDP-43 immunoreactivity in AD was associated with granular and filamentous cytosolic material and only occasionally associated with tau filaments. Western blots of AD cases showed a band that migrated at a higher molecular weight than normal TDP-43 that was not present in AD cases without TDP-43 immunoreactivity. Interpretation These results suggest that as many as 20% of AD cases and more than 70% of HpScl cases have pathology similar to that found in FTLD-U. Whether this represents concomitant FTLD-U or is analogous to colocalization of α-synuclein and tau in AD, reflecting a propensity for codeposition of abnormal protein conformers, remains to be determined. Ann Neurol 2007;61:435–445

753 citations

Journal ArticleDOI
TL;DR: Results indicate that TDP-43 is capable of modulating both in vitro and in vivo HIV-1 gene expression by either altering or blocking the assembly of transcription complexes that are capable of responding to Tat.
Abstract: Human immunodeficiency virus type 1 (HIV-1) gene expression is modulated by both viral and cellular factors. A regulatory element in the HIV-1 long terminal repeat known as TAR, which extends from nucleotides -18 to +80, is critical for the activation of gene expression by the transactivator protein, Tat. RNA transcribed from TAR forms a stable stem-loop structure which serves as the binding site for both Tat and cellular factors. Although TAR RNA is critical for Tat activation, the role that TAR DNA plays in regulating HIV-1 gene expression is not clear. Several studies have demonstrated that TAR DNA can bind cellular proteins, such as UBP-1/LBP-1, which repress HIV-1 gene expression and other factors which are involved in the generation of short, nonprocessive transcripts. In an attempt to characterize additional cellular factors that bind to TAR DNA, a lambda gt11 expression cloning strategy involving the use of a portion of TAR DNA extending from -18 to +28 to probe a HeLa cDNA library was used. We identified a cDNA, designated TAR DNA-binding protein (TDP-43), which encodes a cellular factor of 43 kDa that binds specifically to pyrimidine-rich motifs in TAR. Antibody to TDP-43 was used in gel retardation assays to demonstrate that endogenous TDP-43, present in HeLa nuclear extract, also bound to TAR DNA. Although TDP-43 bound strongly to double-stranded TAR DNA via its ribonucleoprotein protein-binding motifs, it did not bind to TAR RNA extending from +1 to +80. To determine the function of TDP-43 in regulating HIV-1 gene expression, in vitro transcription analysis was performed. TDP-43 repressed in vitro transcription from the HIV-1 long terminal repeat in both the presence and absence of Tat, but it did not repress transcription from other promoters such as the adenovirus major late promoter. In addition, transfection of a vector which expressed TDP-43 resulted in the repression of gene expression from an HIV-1 provirus. These results indicate that TDP-43 is capable of modulating both in vitro and in vivo HIV-1 gene expression by either altering or blocking the assembly of transcription complexes that are capable of responding to Tat.

707 citations

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