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

Frontotemporal lobar degeneration, corticobasal degeneration (CBD), progressive supranuclear palsy, and amyotrophic lateral sclerosis have been considered distinct clinicopathologic entities with few issues in common other than neurodegeneration being central to all. The aim of this paper is to highlight the clinical, topographic, pathologic, proteomic, and genetic similarities among these disorders and the syndromes through which each disorder is exhibited. The critical roles of tau and TAR DNA-binding protein 43 (TDP-43) dysfunction in the disorders and syndromes are emphasized. Although confusion certainly remains, and the ability to predict the underlying proteinopathy in the various neurodegenerative syndromes is far from perfect, there is optimism that insights gained over the next few years will enhance our ability to accurately identify the amyloidopathies, tauopathies, and TDP-43opathies early in the disease course, potentially improving the ability to impact these diseases once targeted therapies have been developed.
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PMID:Links between frontotemporal lobar degeneration, corticobasal degeneration, progressive supranuclear palsy, and amyotrophic lateral sclerosis. 1809 Apr 21

The TAR DNA-binding protein-43 (TDP-43) has been identified as a major constituent of inclusions found in frontotemporal dementia with ubiquitin-positive inclusions (FTLD-U) and amyotrophic lateral sclerosis (ALS). To determine a possible role for TDP-43 in Alzheimer's disease (AD), a site-directed caspase-cleavage antibody to TDP-43 based upon a known caspase-3 cleavage consensus site within TDP- 43 at position D219 was designed. In vitro, this antibody labeled the predicted 25 kDa caspase-cleavage fragment of TDP-43 without labeling full-length TDP-43 following digestion of recombinant TDP-43 with caspase-3 or treatment of HeLa cells with staurosporine. Application of this antibody in postmortem brain sections indicated the presence of caspase-cleaved TDP-43 in Hirano bodies, tangles, reactive astrocytes and neuritic plaques of the AD brain. Caspase-cleaved TDP-43 also co-localized with ubiquitin labeled neurons as well as dystrophic neurites within plaque regions. These results suggest that caspase-cleaved TDP-43 is a major pathological finding in AD and may contribute to the neurodegeneration associated with this disease.
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PMID:Caspase-cleaved TAR DNA-binding protein-43 is a major pathological finding in Alzheimer's disease. 1863 62

TAR DNA binding protein 43 (TDP-43) has been considered a signature protein in frontotemporal dementia and amyotrophic lateral sclerosis (ALS), but not in ALS associated with the superoxide dismutase 1 (SOD1) gene mutations (ALS1). To clarify how TDP may be involved in ALS pathogenesis, clinical and pathological features in cases of sporadic ALS ([SALS] n = 18) and ALS1 (n = 6) were analyzed. In SALS patients with rapid clinical courses, TDP mislocalization (i.e. cytoplasmic staining and TDP-positive cytoplasmic inclusions) in anterior horn cells was frequent. In SALS patients with slow clinical courses, TDP-43 mislocalization was rare. In an ALS1 patient with the SOD1 gene mutation C111Y, there were numerous TDP-positive inclusions and colocalization of SOD1 and TDP. In mutant SOD1 transgenic (G93A) mice at the end stage (median, 256 days), TDP-positive inclusions and TDP colocalization with SOD1 were also observed; nuclear TDP-43 immunoreactivity was highly correlated with life span in these mice. In both humans and mice, nuclei that stained strongly for TDP were large and circular; weakly stained nuclei were atrophic or deformed. In conclusion, low levels of TDP expression in the nucleus cor relate with a rapid clinical course in SALS and in ALS1 model mice, suggesting that nuclear TDP may play a protective role against motor neuron death resulting from different underlying etiologies.
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PMID:Nuclear TAR DNA binding protein 43 expression in spinal cord neurons correlates with the clinical course in amyotrophic lateral sclerosis. 1910 47

Pathological modifications in the highly conserved and ubiquitously expressed heterogeneous ribonucleoprotein TDP-43 were recently associated to neurodegenerative diseases including amyotrophic lateral sclerosis (ALS), a late-onset disorder that affects predominantly motoneurons [Neumann, M. et al. (2006) Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 314, 130-133, Sreedharan, J. et al. (2008) TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis. Science 319, 1668-1672, Kabashi, E. et al. (2008) TARDBP mutations in individuals with sporadic and familial amyotrophic lateral sclerosis. Nat. Genet. 40, 572-574]. However, the function of TDP-43 in vivo is unknown and a possible direct role in neurodegeneration remains speculative. Here, we report that flies lacking Drosophila TDP-43 appeared externally normal but presented deficient locomotive behaviors, reduced life span and anatomical defects at the neuromuscular junctions. These phenotypes were rescued by expression of the human protein in a restricted group of neurons including motoneurons. Our results demonstrate the role of this protein in vivo and suggest an alternative explanation to ALS pathogenesis that may be more due to the lack of TDP 43 function than to the toxicity of the aggregates.
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PMID:Depletion of TDP-43 affects Drosophila motoneurons terminal synapsis and locomotive behavior. 1937 45

Pathogenic mutations in the gene encoding TDP-43, TARDBP, have been reported in familial amyotrophic lateral sclerosis (FALS) and, more recently, in families with a heterogeneous clinical phenotype including both ALS and frontotemporal lobar degeneration (FTLD). In our previous study, sequencing analyses identified one variant in the 3'-untranslated region (3'-UTR) of the TARDBP gene in two affected members of one family with bvFTD and ALS and in one unrelated clinically assessed case of FALS. Since that study, brain tissue has become available and provides autopsy confirmation of FTLD-TDP in the proband and ALS in the brother of the bvFTD-ALS family and the neuropathology of those two cases is reported here. The 3'-UTR variant was not found in 982 control subjects (1,964 alleles). To determine the functional significance of this variant, we undertook quantitative gene expression analysis. Allele-specific amplification showed a significant increase of 22% (P < 0.05) in disease-specific allele expression with a twofold increase in total TARDBP mRNA. The segregation of this variant in a family with clinical bvFTD and ALS adds to the spectrum of clinical phenotypes previously associated with TARDBP variants. In summary, TARDBP variants may result in clinically and neuropathologically heterogeneous phenotypes linked by a common molecular pathology called TDP-43 proteinopathy.
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PMID:TARDBP 3'-UTR variant in autopsy-confirmed frontotemporal lobar degeneration with TDP-43 proteinopathy. 1961 95

TAR DNA-binding protein of about 43 kDa (TDP-43) is the main ubiquitinated peptide in tau-negative frontotemporal lobar degeneration (FTLD). TDP-43 is typically a nuclear protein, and its aggregation and cytoplasmic translocation are thought to represent major steps in the pathogenesis of FTLD due to TDP-43 proteinopathy (FTLD-TDP). Certain clinical syndromes of frontotemporal dementia are preferentially associated with pathologic findings of FTLD-TDP, and TDP-43 pathology represents the connection between FTLD-TDP and amyotrophic lateral sclerosis. Recent advances in clinical, genetic, and pathologic studies of FTLD-TDP and amyotrophic lateral sclerosis have shed light on the potentially pathogenic role of TDP-43 and identified TDP-43 itself as a candidate biomarker for antemortem diagnosis of FTLD-TDP.
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PMID:TDP-43 and frontotemporal dementia. 1966 64

The molecular pathogenesis of amyotrophic lateral sclerosis (ALS) is unclear. TAR DNA-binding proteins of 43 kDa (TDP-43) -positive-cytoplasmic inclusions have been found in the glia and neurons of ALS patients. TDP-43 -positive inclusions have been reported in several neurodegenerative disorders other than ALS. Therefore it is not clear whether TDP-43 plays a primary role in the pathogenesis of ALS. The discovery of TDP-43 mutations in ALS patients indicates that TDP-43 plays a pivotal role in the pathogenesis of ALS. More than 30 mutations in the TDP-43 gene have been identified in patients with familial and sporadic ALS. ALS with a TDP-43 mutation is classified as ALS-10. The clinical features of ALS-10 are quite similar to those of sporadic ALS. Furthermore, the neuropathological findings for ALS-10, including TDP-43 -positive inclusions and Bunina bodies, are identical to those in sporadic ALS; these findings indicate that the study of ALS-10 may lead to a better understanding of sporadic ALS. Most of the mutations are located in the C-terminus of TDP-43, which may function as a binding domain for heterogeneous nuclear ribonucleoprotein. Biochemical analyses of TDP-43 in sporadic ALS patients indicate that the TDP-43 is truncated, and the C-terminus is phosphorylated forming insoluble inclusions in the neurons and glia. In certain ALS-10 cases, missense mutated TDP-43s tend to be truncated and form inclusions. The cytotoxicity of these mutated TDP-43s has also been reported; however, these results are still controversial. Therefore, further analysis is required to elucidate the molecular mechanism underlying the development of ALS-10.
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PMID:[The implications of TDP-43 mutations in pathogenesis of amyotrophic lateral sclerosis]. 1993 87

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

Transactive response (TAR) DNA-binding protein 43 (TDP-43) is a major protein component within ubiquitin-positive inclusions of frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Although TDP-43 is a nuclear DNA/RNA-binding protein, in pathological conditions, TDP-43 has been reported to redistribute to the cytoplasm where it is cleaved and forms insoluble, ubiquitinated, and phosphorylated inclusions. Here we present a cellular model in which full-length human TDP-43 or a splicing isoform (TDP-S6) that lacks the C terminus is overexpressed in a human cell line and mouse primary neurons. Whereas recombinant and endogenous TDP-43 was primarily localized in the nucleus, the shorter TDP-S6 formed highly insoluble cytoplasmic and nuclear inclusions reminiscent of disease-specific pathology. Western blot analysis of detergent-insoluble extracts showed an increase in high molecular weight immunoreactive species for TDP-S6 compared with TDP-43, consistent with ubiquitination or ubiquitin-like modifications. We used a multiplex stable isotope labeling with amino acids in cell culture approach to compare the detergent-insoluble proteome from mock-, TDP-43-, and TDP-S6-transfected cells. TDP-S6 overexpression caused a concomitant increase in both ubiquitin (Ub) and the small Ub-like modifier-2/3 (SUMO-2/3) within the insoluble proteome. Similarly, full-length TDP-43 overexpression also resulted in the elevation of SUMO-2/3. Immunofluorescence showed strong co-localization of endogenous Ub with both cytoplasmic and nuclear TDP-S6 inclusions, whereas SUMO-2/3 was co-localized mainly with the nuclear inclusions. Quantitative mass spectrometry further revealed that mixed Lys-48 and Lys-63 polyUb linkages were associated with the TDP insoluble fractions. Together our data indicate that expression of a TDP-43 splice variant lacking a C terminus recapitulates many of the cellular and biochemical features associated with disease pathology and that the interplay of ubiquitination and SUMOylation may have an important role in TDP-43 regulation.
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PMID:Multiplex SILAC analysis of a cellular TDP-43 proteinopathy model reveals protein inclusions associated with SUMOylation and diverse polyubiquitin chains. 2004 51


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