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)

The only specific marker of sporadic amyotrophic lateral sclerosis (ALS) is neuropathologic, namely the presence of inclusions staining positively for ubiquitin and TAR DNA-binding protein (TARDBP, also known as TDP-43) in degenerating motor neurons. Abnormalities in various physiopathologic pathways associated with ALS, such as oxidative stress, inflammation, and excitotoxicity, have been reported in blood, cerebrospinal fluid, and muscle biopsies. A number of studies in ALS patients have indicated that nuclear magnetic resonance (NMR) spectroscopy and diffusion tensor magnetic resonance imaging (MRI) can detect corticospinal lesions. However, because of their relative lack of sensitivity and specificity, these techniques are currently inadequate for use as diagnostic tools in individual patients. Recently, there has been much interest in the use of high-throughput techniques such as transcriptomics, proteomics, and metabolomics for the detection of biomarkers. In the future, a combination of biologic, radiologic, and electrophysiologic markers, rather than a single marker, may prove a useful tool for the diagnosis and follow-up of ALS patients. This article provides an overview of recently described biologic and radiologic markers of the disease.
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PMID:Biomarkers in amyotrophic lateral sclerosis: facts and future horizons. 1953 46

TAR-DNA-binding protein 43 (TDP-43) was considered to be a disease-specific component of ubiquitin-positive and tau-negative inclusions in the brains of patients with frontotemporal lobar degeneration and amyotrophic lateral sclerosis (ALS). However, this protein also accumulates abnormally in neurons in other neurodegenerative diseases, including Alzheimer's disease (AD). Although the role of TDP-43 deposition in these diseases is not clear, abnormal phosphorylation of the protein is suggested to be a critical step in disease pathogenesis. In this study, we generated a new phosphorylation-dependent TDP-43 antibody and examined AD brain sections from temporal lobes, including the hippocampus and temporal neocortex, by immunohistochemistry. The antibody, called A2, specifically recognized phosphorylated TDP-43 in western blotting using ALS and AD specimens, detecting a strong 45kDa band and several shorter fragments at around 25kDa with smears. Immunohistochemistry demonstrated neuronal cytoplasmic inclusions in AD brain sections without staining nuclei that were normal physiological TDP-43 localization sites. These results were consistent with previous reports. However, intraneuronal dot-like structures were also intensely labeled by immunohistochemistry. These structures were observed in all the AD brain sections examined and also occurred in sections from the brains of aged subjects without AD pathologies. The morphological and immunohistochemical characteristics of these granular structures were compatible with those of granulovacuolar degeneration (GVD). The A2 antibody clearly and intensely detected granular structures distributed over the hippocampus, subiculum, parahippocampus and temporal neocortex. Thus, immunohistochemistry using phosphorylation-dependent TDP-43 antibodies would be a new useful tool for identifying GVD.
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PMID:Phosphorylation-dependent TDP-43 antibody detects intraneuronal dot-like structures showing morphological characters of granulovacuolar degeneration. 1953 3

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

Both, amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U), and their combination (FTLD-U/MND) are principally sporadic diseases that are rarely familial. Cytoplasmic ubiquitinated proteinaceous inclusions in motor and extra-motor neurons are the pathological hallmark of all three forms. In 2006, the TAR DNA-binding protein of 43 kDa (TDP-43) was both identified as the key protein component of the ubiquitinated inclusions and recognised as the key protein of a spectrum of diseases that have since been consolidated as TDP-43 proteinopathies. TDP-43 as a nuclear protein contributes to the regulation of gene expression, and associated with neurodegeneration, it has been found to be truncated, hyperphosphorylated, and mislocalized. It is unclear whether the loss of the TDP-43's nuclear function or the gain of a toxic function outside its nucleus is disease causing. Since 2008, several TARDBP-mutations have been identified as leading to the autosomal-dominant familial ALS (ALS 10), although no TARDBP-mutations have yet to be linked to FTLD.
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PMID:[TDP-43 proteinopathies: ALS and frontotemporal dementias]. 1968 86

The mechanisms underlying selective motor neuron degeneration in amyotrophic lateral sclerosis (ALS) remain unknown. There have been several important clinical trials on the treatment of ALS and treatment efficacy studies using mouse (SOD1) models of ALS. The latter revealed that diminished mutant SOD1 expression in the astrocytes delayed microglial activation and slowed disease progression. Dyslipidemia has been reported to have a protective effect in ALS patients. Current evidence has implicated a 43-kDa TAR DNA-binding protein (TDP-43) in the pathologenesis of ALS. Several mutations in TDP-43 were discovered in families with inherited motor neuron disease. Although phase III trials revealed that creatine monohydrate and IGF-1 was not beneficial for patients with ALS, favorable outcomes in SOD1 mice were reported with lithium, NADPH oxidase inhibitor, free-radical scavenger, and ammonium tetrathiomolybdate. Spinal and bulbar muscular atrophy (SBMA) is an adult-onset motor neuron disease affecting only males. Animal studies have revealed that the pathogenesis of SBMA depends on the serum testosterone level and that androgen deprivation mitigates neurodegeneration through inhibition of nuclear accumulation of the pathogenic androgen receptor (AR). Our studies have also identified several candidates for the treatment of SBMA. Selective inhibition of heat shock protein (HSP) facilitates the proteasomal degradation of pathogenic AR, leading to improvements in the signs and symptoms of SBMA mice. Oral administration of sodium butyrate--a histone deacetylase inhibitor--resulted in the improvement of neurological dysfunction in the SBMA mouse model, although its therapeutic dose range is narrow.
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PMID:[Molecular-targeted therapy for motor neuron disease]. 1969 78

Amyotrophic lateral sclerosis (ALS) is the most common adult motor neuron disease that affects approximately 2/100,000 individuals each year worldwide. Patients with ALS suffer from rapidly progressive degeneration of motor neurons ultimately leading to death. The major pathological features observed in post-mortem tissue from patients with ALS are motor neuron loss, cortical spinal tract degeneration, gliosis and cytoplasmic neuronal inclusions formed by TDP-43 or TAR DNA binding Protein with a molecular mass of 43 kDa, which are now recognized as the signature lesions of sporadic ALS. TDP-43 possesses two RNA binding domains (RBD) and a glycine-rich C terminus classifying it with other heterogeneous nuclear ribonucleoproteins known as 2XRBD-Gly proteins. A number of reports showed that a subset of patients with ALS possess mutations in the TDP-43 (TARDBP) gene. This further strengthens the hypotheses that gain of toxic function or loss of function in TDP-43 causes ALS. Currently, 29 different TARDBP missense mutations have been reported in 51 unrelated sporadic or familial ALS cases and two cases of ALS plus concomitant frontotemporal lobar degeneration with a remarkable concentration of mutations in the C-terminal glycine-rich domain of TDP-43. As these mutations will most certainly be an invaluable tool for the design and implementation of ALS animal and cell models, as well as serve as a platform for exploring the pathobiology of TDP-43, here we summarize the identified pathogenic TARDBP mutations and their potential impact on our understanding of the role of TDP-43 in disease.
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PMID:Mutations in TDP-43 link glycine-rich domain functions to amyotrophic lateral sclerosis. 1980 91

Cystatin C (CC), a cysteine protease inhibitor involved in protein degradation, is a marker of Bunina bodies in lower motor neurons in amyotrophic lateral sclerosis (ALS). TAR-DNA binding protein-43 (TDP-43)-immunoreactive inclusions are also histological hallmarks of ALS but whether CC is found in motor neurons with or without TDP-43-positive inclusions in ALS is not known. To determine whether inclusion body formation affects cytoplasmic CC immunoreactivity, we examined spinal cords from 9 ALS patients and 12 control subjects by immunohistochemistry. Most anterior horn cells (AHCs) showed moderate to intense immunoreactivity in controls, whereas CC immunoreactivity was markedly decreased in AHCs in ALS cases. The proportion of CC-immunolabeled AHCs was reduced regardless of whether they contained Bunina bodies. In contrast, the proportion of CC-immunolabeled AHCs was significantly reduced in those with TDP-43 inclusions. Cystatin C immunoreactivity of astrocytes in the spinal gray matter and white matter in ALS was significantly decreased compared with controls. These findings suggest that the formation of TDP-43 inclusions, but not of Bunina bodies, may be linked to the content of CC in spinal motor neurons and that perturbations in endogenous levels of CC in neuronal and glial cells may be part of the neurodegenerative processes in ALS.
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PMID:Decreased cystatin C immunoreactivity in spinal motor neurons and astrocytes in amyotrophic lateral sclerosis. 1981 97

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

TDP-43 (43-kDa TAR DNA-binding protein) is a major constituent of ubiquitin-positive cytosolic aggregates present in neurons of patients with amyotrophic lateral sclerosis (ALS) and ubiquitin-positive fronto-temporal lobar degeneration (FTLD-U). Inherited mutations in TDP-43 have been linked to familial forms of ALS, indicating a key role for TDP-43 in disease pathogenesis. Here, we describe a Drosophila melanogaster model of TDP-43 proteinopathy. Expression of wild-type human TDP-43 protein in Drosophila motor neurons led to motor dysfunction and dramatic reduction of life span. Interestingly, coexpression of ubiquilin 1, a previously identified TDP-43-interacting protein with suspected functions in autophagy and proteasome targeting, reduced steady-state TDP-43 expression but enhanced the severity of TDP-43 phenotypes. Finally, ectopically expressed TDP-43 was largely localized to motor neuron nuclei, suggesting that expression of wild-type TDP-43 alone is detrimental even in the absence of cytosolic aggregation. Our findings demonstrate that TDP-43 exerts cell-autonomous neurotoxicity in Drosophila and further imply that dose-dependent alterations of TDP-43 nuclear function may underlie motor neuron death in ALS.
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PMID:Ubiquilin modifies TDP-43 toxicity in a Drosophila model of amyotrophic lateral sclerosis (ALS). 2015 90

The clinical features of a Japanese family with autosomal dominant adult-onset amyotrophic lateral sclerosis (ALS) are reported. Weakness initially affected the bulbar musculature, with later involvement of the extremities. Genetic studies failed to detect any mutations of the Cu/Zn superoxide dismutase-1 (SOD1) and Dynactin1 (DCTN1) genes, but revealed a single base pair change from wild-type adenine to guanine at position 1009 in TAR-DNA-binding protein (TDP-43), resulting in a methionine-to-valine substitution at position 337. The immunohistochemical study on autopsied brain of the proband's aunt showed TDP-43-positive cytoplasmic inclusions in the anterior horn cells of the spinal cord and in the hypoglossal nucleus, as well as glial cytoplasmic inclusions in the precentral gyrus, suggesting that a neuroglial proteinopathy was related to TDP-43. In conclusion, a characteristic clinical phenotype of familial ALS with initial bulbar symptoms occurred in this family with TDP-43 M337V substitution, the pathomechanism of which should be elucidated.
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PMID:TDP-43 M337V mutation in familial amyotrophic lateral sclerosis in Japan. 2015 40


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