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)

TDP-43 is now known to be a major component of ubiquitin-positive, tau-negative inclusions in frontotemporal lobar degeneration with ubiquitin-positive inclusions and sporadic amyotrophic lateral sclerosis. In this study, we mapped the epitope for the monoclonal anti-TDP-43 antibody 2E2-D3. Our mapping and peptide competition experiments showed that the antibody reacted with human TDP-43, but not mouse or rat TDP-43, and recognized amino acids 205-222 of human TDP-43, corresponding to a part of the second RNA recognition motif. These findings suggest that 2E2-D3 is a useful antibody for the characterization of mouse lines transgenic for human TDP-43.
 ...
PMID:Epitope mapping of 2E2-D3, a monoclonal antibody directed against human TDP-43. 1830 32

TDP-43 (for TAR DNA binding protein) is a highly conserved heterogeneous nuclear ribonucleoprotein (hnRNP) involved in specific pre-mRNA splicing and transcription events. TDP-43 recently has been identified as the main component of cytoplasmic inclusions in frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS), two neurodegenerative disorders. The cellular role of this protein remains to be identified. Here, we show that loss of TDP-43 results in dysmorphic nuclear shape, misregulation of the cell cycle, and apoptosis. Removal of TDP-43 in human cells significantly increases cyclin-dependent kinase 6 (Cdk6) protein and transcript levels. The control of Cdk6 expression mediated by TDP-43 involves GT repeats in the target gene sequence. Cdk6 up-regulation in TDP-43-depleted cells is accompanied by an increase in phosphorylation of two of its major targets, the retinoblastoma protein pRb and pRb-related protein pRb2/p130. TDP-43 silencing also is followed by changes in the expression levels of several factors that control cell proliferation. Morphological nuclear defects and increased apoptosis upon TDP-43 loss are mediated via the pRb pathway because pRb-negative cells (Saos-2) do not undergo programmed cell death or nuclear shape deformation upon TDP-43 removal. Our results identify a regulatory target of TDP-43 and show that TDP-43 depletion has important consequences in essential metabolic processes in human cells.
 ...
PMID:TDP-43 regulates retinoblastoma protein phosphorylation through the repression of cyclin-dependent kinase 6 expression. 1830 52

Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disorder characterized pathologically by ubiquitinated TAR DNA binding protein (TDP-43) inclusions. The function of TDP-43 in the nervous system is uncertain, and a mechanistic role in neurodegeneration remains speculative. We identified neighboring mutations in a highly conserved region of TARDBP in sporadic and familial ALS cases. TARDBPM337V segregated with disease within one kindred and a genome-wide scan confirmed that linkage was restricted to chromosome 1p36, which contains the TARDBP locus. Mutant forms of TDP-43 fragmented in vitro more readily than wild type and, in vivo, caused neural apoptosis and developmental delay in the chick embryo. Our evidence suggests a pathophysiological link between TDP-43 and ALS.
 ...
PMID:TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis. 1830 45

Frontotemporal lobar degeneration with ubiquitinated inclusions (FTLD-U) is the most common neuropathology associated with the clinical syndrome of frontotemporal dementia (FTD). Recently, TDP-43 was identified as the ubiquitinated pathological protein in both FTLD-U and sporadic amyotrophic lateral sclerosis. Although a number of studies have now confirmed that most sporadic and familial cases of FTLD-U are TDP-43 proteinopathies, there are exceptions. We describe six cases of early onset FTD with FTLD-U pathology that was negative for TDP-43, which we refer to as 'atypical' FTLD-U. All cases were sporadic and had very early onset FTD (mean age = 35 years), characterized by severe progressive psychobehavioural abnormalities in the absence of significant aphasia, cognitive-intellectual dysfunction or motor features. The neuropathological features were highly consistent, with small, round, neuronal cytoplasmic inclusions that were immunoreactive for ubiquitin (ub-ir), but negative for tau, alpha-synuclein, intermediate filaments and TDP-43. Cytoplasmic inclusions were most numerous in the neocortex, dentate granule cells and hippocampal pyramidal neurons. Ub-ir neuronal intra-nuclear inclusions were also present in neocortical and hippocampal neurons and had the unusual appearance of straight, curved or twisted filaments. We believe that these cases represent a new entity that is clinically and pathologically distinct from all currently recognized subtypes of FTLD. Moreover, the existence of such cases indicates that the designations of 'FTLD-U' and 'TDP-43 proteinopathy' should not be considered to be synonymous.
 ...
PMID:Atypical frontotemporal lobar degeneration with ubiquitin-positive, TDP-43-negative neuronal inclusions. 1836 96

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.
 ...
PMID:TARDBP mutations in individuals with sporadic and familial amyotrophic lateral sclerosis. 1837 2

Mutations in the endosomal sorting complexes required for transport (ESCRT)-III subunit CHMP2B are associated with frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), both human neurodegenerative diseases characterized by accumulation of ubiquitinated proteins aggregates in affected neurons. The ESCRT proteins are known to be involved in diverse cellular processes such as mRNA transport, cytokinesis, transcriptional regulation and sorting of transmembrane proteins into the inner vesicles of the multivesicular body (MVB) during endocytosis. It was until recently not clear how ESCRT function may be involved in neurodegeneration. New findings in mammalian cells and in Drosophila melanogaster show that functional ESCRTs are required for efficient fusion of autophagic vesicles with the endocytic pathway and for degradation of autophagic cargo. Moreover, defective ESCRT function led to the accumulation of cytoplasmic protein aggregates containing ubiquitin, p62/Sequestosome-1 and TAR DNA binding protein 43 (TDP-43). Using cellular and Drosophila models for Huntington's disease it was also shown that reduced ESCRT levels inhibit clearance of expanded polyglutamine aggregates and aggravate their neurotoxic effect. These data indicate that efficient autophagic degradation requires functional MVBs and provides a possible explanation to the observed neurodegenerative phenotype seen in patients with CHMP2B mutations.
 ...
PMID:ESCRT functions in autophagy and associated disease. 1841 46

Protein misfolding is intimately associated with devastating human neurodegenerative diseases, including Alzheimer's, Huntington's, and Parkinson's. Although disparate in their pathophysiology, many of these disorders share a common theme, manifested in the accumulation of insoluble protein aggregates in the brain. Recently, the major disease protein found in the pathological inclusions of two of these diseases, amyotrophic lateral sclerosis (ALS) and frontal temporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U), was identified as the 43-kDa TAR-DNA-binding protein (TDP-43), providing a molecular link between them. TDP-43 is a ubiquitously expressed nuclear protein that undergoes a pathological conversion to an aggregated cytoplasmic localization in affected regions of the nervous system. Whether TDP-43 itself can convey toxicity and whether its abnormal aggregation is a cause or consequence of pathogenesis remain unknown. We report a yeast model to define mechanisms governing TDP-43 subcellular localization and aggregation. Remarkably, this simple model recapitulates several salient features of human TDP-43 proteinopathies, including conversion from nuclear localization to cytoplasmic aggregation. We establish a connection between this aggregation and toxicity. The pathological features of TDP-43 are distinct from those of yeast models of other protein-misfolding diseases, such as polyglutamine. This suggests that the yeast model reveals specific aspects of the underlying biology of the disease protein rather than general cellular stresses associated with accumulating misfolded proteins. This work provides a mechanistic framework for investigating the toxicity of TDP-43 aggregation relevant to human disease and establishes a manipulable, high-throughput model for discovering potential therapeutic strategies.
 ...
PMID:A yeast TDP-43 proteinopathy model: Exploring the molecular determinants of TDP-43 aggregation and cellular toxicity. 1843 38

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder. Accumulating evidence has shown that 43kDa TAR-DNA-binding protein (TDP-43) is the disease protein in ALS and frontotemporal lobar degeneration. We previously reported a familial ALS with Bumina bodies and TDP-43-positive skein-like inclusions in the lower motor neurons; these findings are indistinguishable from those of sporadic ALS. In three affected individuals in two generations of one family, we found a single base-pair change from A to G at position 1028 in TDP-43, which resulted in a Gln-to-Arg substitution at position 343. Our findings provide a new insight into the molecular pathogenesis of ALS.
 ...
PMID:TDP-43 mutation in familial amyotrophic lateral sclerosis. 1843 52

A nuclear protein, 43-kDa TAR DNA-binding protein (TDP-43), was recently identified as a component of the ubiquitinated inclusions (UIs) in frontotemporal lobar degeneration (FTLD-U) and sporadic amyotrophic lateral sclerosis (SALS). In the present study using immunohistochemistry, we examined various regions of the nervous system in a series of 35 SALS cases using a polyclonal antibody against TDP-43. Seven of the 35 cases had disease durations of more than 10 years with artificial respiratory support (ARS; duration: 69-156 months). In all cases, TDP-43-immunoreactive (ir) neuronal and glial cytoplasmic inclusions (NCIs and GCIs) were found together in many regions, including the histologically affected lower motor neuron nuclei. Cluster analysis of the distribution pattern of TDP-43-ir NCIs for cases without ARS (n = 28) identified two types (type 1, n = 16; type 2, n = 12). Type 2 was distinguished from type 1 by the presence of TDP-43-ir NCIs in the frontotemporal cortex, hippocampal formation, neostriatum and substantia nigra, and was significantly associated with dementia. Eleven of the 28 cases showed UIs in the hippocampal dentate granule cells, all of which had type-2 distribution pattern. Cases with ARS (n = 7) were also classified into the same types (type 1, n = 5; type 2, n = 2). Cases having type-1 distribution pattern (n = 21) showed no evident neuronal loss in most of the non-motor neuron nuclei where TDP-43-ir NCIs were present, whereas cases having type-2 distribution pattern (n = 14) often showed evident neuronal loss in the frontotemporal cortices, amygdaloid nuclei and substantia nigra. These findings indicate that SALS is a multisystem degenerative disease widely affecting both neurons and glial cells with a heterogeneous pattern of TDP-43-ir NCI distribution (SALS showing type-2 distribution pattern being closely linked to FTLD-U), and that long-term survival supported by a respirator has no apparent influence on the TDP-43 neuronal distribution pattern.
 ...
PMID:Sporadic amyotrophic lateral sclerosis: two pathological patterns shown by analysis of distribution of TDP-43-immunoreactive neuronal and glial cytoplasmic inclusions. 1848 Oct 73

There is a high incidence on Guam of a severe tauopathy known as the Parkinson- dementia complex (PDC). It is linked with an even more malignant amyotrophic lateral sclerosis (ALS) syndrome. There is great interest in determining the cause, or causes, of the Guam ALS/PDC syndrome because insight might be gained regarding ALS and the more common tauopathies found throughout the world. Research into the disorder is stimulated by hypotheses as to cause. Such hypotheses should be compatible with the known epidemiology and pathology of the syndrome. These include a high, if not exclusive, restriction to the Chamorro population, familial occurrence, a regional variation on Guam itself, a definite persistence but with declining incidence, and a possible duplication in isolated villages on the Kii peninsula of Japan. Proposed causation factors should also be able to reproduce the syndrome in experimental systems. This includes induction of neurofibrillary tangles with a tau isoform distribution similar to that of Alzheimer disease and association of the lesions with TDP-43 and Lrrk2. A recurring hypothesis as to causation is exposure to Cycas micronesica, the false Sago palm known locally as fadang. We review the reasons why this hypothesis falls short of the minimal criteria needed for further serious consideration and discuss some other possibilities that should not be excluded.
 ...
PMID:The ALS/PDC syndrome of Guam and the cycad hypothesis. 1919 86


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>