Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0002736 (amyotrophic lateral sclerosis)
 19,048 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
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PMID:Mutations in the FUS/TLS gene on chromosome 16 cause familial amyotrophic lateral sclerosis. 1925 27

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder with a low survival rate beyond 5 years from symptom onset. Although the genes that cause most cases of ALS are still unknown, several important genetic discoveries have been made recently that will bring substantial insight into some of the mechanisms involved in ALS. Mutations in two genes with related functions were recently reported in patients with familial ALS: the FUS/TLS gene at the ALS6 locus on chromosome 16 and the TARDBP gene at the ALS10 locus on chromosome 1. In addition, the first wave of genomewide association studies in ALS has been published. While these studies clearly show that there is no definitive and common highly penetrant allele that causes ALS, some interesting candidate genes emerged from these studies. The findings help to better delineate the types of genes and genetic variants that are involved in ALS and provide substantial material for future research.
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PMID:Recent advances in the genetics of amyotrophic lateral sclerosis. 1934 8

Inclusions of TAR DNA-binding protein-43 (TDP-43), a nuclear protein that regulates transcription and RNA splicing, are the defining histopathological feature of frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-Us) and sporadic and familial forms of amyotrophic lateral sclerosis (ALS). In ALS and FTLD-U, aggregated, ubiquitinated, and N-terminally truncated TDP-43 can be isolated from brain tissue rich in neuronal and glial cytoplasmic inclusions. The loss of TDP-43 function resulting from inappropriate cleavage, translocation from the nucleus, or its sequestration into inclusions could play important roles in neurodegeneration. However, it is not known whether TDP-43 fragments directly mediate toxicity and, more specifically, whether their abnormal aggregation is a cause or consequence of pathogenesis. We report that the ectopic expression of a approximately 25-kDa TDP-43 fragment corresponding to the C-terminal truncation product of caspase-cleaved TDP-43 leads to the formation of toxic, insoluble, and ubiquitin- and phospho-positive cytoplasmic inclusions within cells. The 25-kDa C-terminal fragment is more prone to phosphorylation at S409/S410 than full-length TDP-43, but phosphorylation at these sites is not required for inclusion formation or toxicity. Although this fragment shows no biological activity, its exogenous expression neither inhibits the function nor causes the sequestration of full-length nuclear TDP-43, suggesting that the 25-kDa fragment can induce cell death through a toxic gain-of-function. Finally, by generating a conformation-dependent antibody that detects C-terminal fragments, we show that this toxic cleavage product is specific for pathologic inclusions in human TDP-43 proteinopathies.
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PMID:Aberrant cleavage of TDP-43 enhances aggregation and cellular toxicity. 1938 87

Peripheral neuropathies are among the most common disorders seen by neuromuscular specialists. Several of the articles in this issue's review focus on diagnosis, treatment, and prognosis of disorders of peripheral nerve, including some which address important issues relating to chronic inflammatory demyelinating polyneuropathy. Motor neuron diseases continue to be somewhat disproportionately represented, likely due to the devastating nature of amyotrophic lateral sclerosis. The TAR DNA-binding protein-43 (TDP-43) story as outlined in 2 of the articles is fascinating, particularly with regard to etiopathogenesis, whereas other articles focus on epidemiology, diagnosis, treatment, and symptom management, including some insights into Kennedy disease. Myotonic dystrophy and other muscle diseases are presented with some welcome news on treatment and management.
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PMID:What's in the Literature? 1949 33

TAR DNA-binding protein-43 (TDP-43) proteinopathies are classified based upon the extent of modified TDP-43 inclusions and include a growing number of neurodegenerative diseases including amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration with ubiquitin immunoreactive, tau negative inclusions (FTLD-U) and FTLD with motor neuron disease (FTLD-MND). In addition, TDP-43 inclusions have also been identified in a number of other neurodegenerative disorders including Alzheimer's disease, corticobasal degeneration, Lewy body related diseases and Pick's disease. Current understanding suggests that in these diseases, TDP-43 is relocated from the nucleus to the cytoplasm and sequestered into inclusions that contain modified TDP-43. Major modifications of TDP-43 have been identified as being hyperphosphorylation and proteolytic cleavage by caspases. In this review a summary of the major findings regarding the proteolytic modification of TDP-43 will be discussed as well as potential toxic-gain mechanisms these fragments may cause including cytoskeletal disruptions.
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PMID:Cytoplasmic inclusions of TDP-43 in neurodegenerative diseases: a potential role for caspases. 1955 15

Cytoplasmic aggregates of ubiquitinated TAR DNA-binding protein 43 (TDP-43) are a pathological hallmark of amyotrophic lateral sclerosis (ALS). However, the mechanism of TDP-43 polyubiquitination remains elusive. We investigated the effect of nuclear exclusion of TDP-43 on aggregate formation and fragmentation, using TDP-43 expression constructs for WT or mutant TDP-43 with a modified nuclear localizing signal (LQ-NLS). Overexpression of the LQ-NLS mutant alone induced no detectable cytoplasmic aggregates during a 72-hr period. Polyubiquitination of both WT TDP-43 and the LQ-NLS mutant was similar in total cell lysates exposed to the proteasome inhibitor lactacystin. However, analysis of subcellular fractions demonstrated a higher concentration of polyubiquitinated TDP-43 in the nuclear fraction than in the cytosol for WT, and vice versa for the LQ-NLS mutant. Polyubiquitin-charged WT and mutant TDP-43 were highly concentrated in the membrane/microsome fraction, which was also positive for the autophagosome marker LC3. In addition, the autophagy inhibitor 3-methyladenine (3MA) blocked degradation of both TDP-43 types, whereas lactacystin was minimally restorative. Furthermore, lactacystin plus 3MA induced prominent cytoplasmic aggregates. We also demonstrated mediation of TDP-43 polyubiquitination by lysine 48 of ubiquitin, indicating a degradation signal in both TDP-43 types. This is the first report delineating the distribution of polyubiquitinated TDP-43 and the degradation pathway of TDP-43 and clarifying the crucial role of autophagosomes in TDP-43 clearance. We also demonstrate that nuclear exclusion itself is not an immediate trigger for ALS pathology. Further clarification of the mechanism of polyubiquitination of TDP-43 and the role of autophagosomes may help in understanding and treating ALS.
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PMID:Synergistic effect between proteasome and autophagosome in the clearance of polyubiquitinated TDP-43. 1979 49

TAR DNA-binding protein-43 (TDP-43) has been recently identified as a major component of the ubiquitinated inclusions found in frontotemporal lobar degeneration with ubiquitin-positive inclusions and in amyotrophic lateral sclerosis, diseases that are collectively termed TDP-43 proteinopathies. Several amyotrophic lateral sclerosis-linked mutations of the TDP-43 gene have also been identified; however, the precise molecular mechanisms underlying the neurodegeneration remain unclear. To investigate the biochemical characteristics of TDP-43, we examined truncation, isoforms, and cytoplasmic inclusion (foci) formation using TDP-43-expressing cells. Under apoptosis, caspase-3 generates two 35-kDa (p35f) and 25-kDa (p25f) fragments. However, in caspase-3(-/-) cells, novel caspase-3-independent isoforms of these two variants (p35iso and p25iso) were also detected under normal conditions. With a deletion mutant series, the critical domains for generating both isoforms were determined and applied to in vitro transcription/translation, revealing alternate in-frame translation start sites downstream of the natural initiation codon. Subcellular localization analysis indicated that p35 (p35f and p35iso) expression leads to the formation of stress granules, cellular structures that package mRNA and RNA-binding proteins during cell stress. After applying proteasome inhibitors, aggresomes, which are aggregates of misfolded proteins, were formed in the cytoplasm of cells expressing p35. Collectively, this study demonstrates that the 35-kDa isoforms of TDP-43 assemble in stress granules, suggesting that TDP-43 plays an important role in translation, stability, and metabolism of mRNA. Our findings provide new biological and pathological insight into the development of TDP-43 proteinopathies.
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PMID:Characterization of alternative isoforms and inclusion body of the TAR DNA-binding protein-43. 1988 43

Frontotemporal lobar degeneration (FTLD) has two pathological types: tau-positive and tau-negative. The most common tau-negative type is FTLD with ubiquitinated inclusions, which are composed of TAR DNA-binding protein-43 (TDP-43) (FTLD-TDP). FTLD-TDP can be subdivided into at least three main types based on the histological patterns of TDP-43-positive neuronal cytoplasmic inclusions (NCI), dystrophic neurites (DN), and neuronal intranuclear inclusions (NII). Type 1 is characterized by the predominance of long, thick DN in the cortices with numerous NCI in the hippocampus, amygdala, and basal ganglia, accompanied by the degeneration of the pyramidal tract in the spinal cord. Type 2 is characterized by numerous NCI in the cortices, associated with the involvement of lower motor neurons. TDP-43-positive skein-like inclusions and round inclusions identical to those observed in amyotrophic lateral sclerosis (ALS) patients are also seen in the lower motor neurons in type 2. Type 3 is characterized by both NCI and DN with variable NII. Lower motor neuron involvement is usually less prominent in types 1 and 3 than in type 2. These findings suggest that FTLD-TDP and ALS are at two ends of the same disease spectrum, i. e., TDP-43 proteinopathy.
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PMID:[Neuropathology of frontotemporal lobar degeneration with ubiquitinated inclusions]. 1993 88

TAR DNA-binding protein-43 (TDP-43) is a nuclear protein functioning in the regulation of transcription and mRNA splicing. TDP-43 is accumulated in ubiquitinated inclusions in frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U) and amyotrophic lateral sclerosis (ALS) diseased brains. However, the pathways involved in the clearance of TDP-43 and its pathogenic form (TDP-25), a truncated form of TDP-43, are still not elucidated. In this study, we demonstrated that the protein levels of TDP-43 and TDP-25 were increased in cells treated with a proteasome inhibitor, MG132, or an autophagy inhibitor, 3-MA, whereas, they were decreased in cells treated with an enhancer of autophagy, trehalose. Furthermore, more protein level changes of TDP-25 than TDP-43 were observed in cells treated with above inhibitors or enhancer. Thus, our data suggest that TDP-43 and TDP-25 are degraded by both proteasome and autophagy with TDP-25 being more regulated.
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PMID:Degradation of TDP-43 and its pathogenic form by autophagy and the ubiquitin-proteasome system. 1994 44

TAR DNA-binding protein-43 (TDP-43) is a 43-kDa nuclear protein involved in regulation of gene expression. Abnormally, phosphorylated, ubiquitinated, and aggregated TDP-43 constitute a principal component of neuronal and glial cytoplasmic and nuclear inclusions in the brains of frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U) and amyotrophic lateral sclerosis (ALS), although the molecular mechanism that triggers aggregate formation remains unknown. By Western blot analysis using anti-TDP-43 antibodies, we identified a band with an apparent molecular mass of 86-kDa in HEK293, HeLa, and SK-N-SH cells in culture. It was labeled with both N-terminal-specific and C-terminal-specific TDP-43 antibodies, enriched in the cytosolic fraction, and the expression levels were reduced by TDP-43 siRNA but unaltered by treatment with MG-132 or by expression of ubiqulin-1 or casein kinase-1. By immunoprecipitation analysis, we found the interaction between the endogenous full-length TDP-43 and the exogenous Flag-tagged TDP-43, and identified the N-terminal half of TDP-43 spanning amino acid residues 3-183 as an intermolecular interaction domain. When the tagged 86-kDa tandemly connected dimer of TDP-43 was overexpressed in HEK293, it was sequestered in the cytoplasm and promoted an accumulation of high-molecular-mass TDP-43-immunoreactive proteins. Furthermore, the 86-kDa band was identified in the immunoblot of human brain tissues, including those of ALS. These results suggest that the 86-kDa band represents dimerized TDP-43 expressed constitutively in normal cells under physiological conditions.
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PMID:TDP-43 dimerizes in human cells in culture. 2004 39


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