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)

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.
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PMID:Mutations in FUS, an RNA processing protein, cause familial amyotrophic lateral sclerosis type 6. 1925 28

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

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

TAR-DNA-binding protein 43 (TDP-43), encoded by the TARDBP gene on chromosome 1p36.22, has been identified as the major pathological protein in abnormal inclusions in neurons and glial cells in sporadic amyotrophic lateral sclerosis (SALS), SOD1-negative familial ALS (FALS) and frontotemporal lobar dementia (FTLD). Twenty mutations of TARDBP in SOD1-negative FALS and SALS cases have been reported so far. To investigate the presence and frequency of TARDBP mutations in Japanese SOD1-negative FALS patients, we performed mutational screening of TARDBP in 30 SOD1-negative FALS patients. An N352S mutation was found in one case of FALS, but no TARDBP mutations were found in cases of SALS. It was thought that this mutation increases TDP-43 phosphorylation. This might lead to impaired nuclear cytoplasmic transport or protein-protein interaction, thereby leading to TDP-43 accumulation.
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PMID:Screening for TARDBP mutations in Japanese familial amyotrophic lateral sclerosis. 1941 Oct 82

Recently, fused in sarcoma/translated in liposarcoma (FUS/TLS) gene, located on chromosome 16p11.2, has been identified as a disease gene in familial amyotrophic lateral sclerosis (FALS). We have analyzed FUS/TLS in a cohort of 52 index cases from seven Italian regions with non-SOD1 and non-TARDBP FALS. We identified a heterozygous c.G1542C missense mutation in a family of northern Italian origin, and a heterozygous c.C1574T missense mutation in a family of Sicilian origin. Both variants are located in exon 15 encoding the RNA-recognition motif, and result in a substitution of an arginine with a serine in position 514 (p.R514S) and substitution of a proline with a leucine at position 525 (p.P525L), respectively. Overall, the two mutations accounted for 3.8% of 52 non-SOD1 and non-TDP43 index cases of FALS. The clinical phenotype was similar within each of the families, with a predominantly upper limb onset in the family carrying the p.R514S mutation and bulbar onset, with very young age and a rapid course in the family carrying the p.P525L mutation.
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PMID:Two Italian kindreds with familial amyotrophic lateral sclerosis due to FUS mutation. 1945 Sep 4

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

TDP-43 has been identified as the pathological protein in the majority of cases of frontotemporal lobar degeneration and amyotrophic lateral sclerosis (ALS). TARDBP mutations have so far been uniquely associated with familial and sporadic ALS. We describe clinicopathological and genetic findings in a carrier of the novel K263E TARDBP variation, who developed frontotemporal dementia, supranuclear palsy, and chorea, but no signs of motor neuron disease. Neuropathologic examination revealed neuronal and glial TDP-43-immunoreactive deposits, predominantly in subcortical nuclei and brainstem. This is the first report of a TARDBP variation associated with a neurodegenerative syndrome other than ALS.
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PMID:TARDBP variation associated with frontotemporal dementia, supranuclear gaze palsy, and chorea. 1960 11

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

It has been recently demonstrated that the 43-kDa transactive response (TAR)-DNA-binding protein (TARDBP) is the neuropathological hallmark of Frontotemporal Dementia (FTD) with ubiquitin-positive and tau-negative inclusions. Large series of FTD patients without motor neuron disease have been previously analysed, but no TARDBP mutation was identified. The aim of the present study was to evaluate whether TARDBP gene mutations may be associated with FTD. We report that a pathogenetic TARDBP mutation is causative of behavioural variant FTD (bvFTD). An aged woman in her seventies initially started to present apathy and depression associated with impairment in executive functions. The diagnosis of bvFTD (apathetic syndrome) was accomplished by three-year follow-up, and structural and functional neuroimaging. By five-years after onset, extensive electrophysiological investigations excluded subclinical motor neuron disease. In this patient, a single base substitution c.800A>G of TARDBP gene was identified. This mutation, already described as causative of ALS, predicted the amino acidic change arginine to serine at position 267 (N267S). In silico analysis demonstrated that this substitution generates a new phosphorylation site, and western blot analysis on lymphoblastoid cells reported a decrease of protein expression in N267S mutation carrier. Our study suggests that TARDBP mutations can be pathogenetic of bvFTD without motor neuron disease. TARDBP screening needs to be considered in FTD cases.
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PMID:Mutation within TARDBP leads to frontotemporal dementia without motor neuron disease. 1965 82

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


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