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

TDP-43 is a RNA/DNA-binding protein structurally related to nuclear hnRNP proteins. Previous biochemical studies have shown that this nuclear protein plays a role in the regulation of gene transcription, alternative splicing and mRNA stability. Despite the ubiquitous distribution of TDP-43, the growing list of TDP-43 proteinopathies is primarily associated with neurodegenerative disorders. Particularly, TDP-43 redistributes to the cytoplasm and forms pathological inclusions in amyotrophic lateral sclerosis and several forms of sporadic and familiar frontotemporal lobar degeneration. Here, we have studied the nuclear compartmentalization of TDP-43 in normal rat neurons by using light and electron microscopy immunocytochemistry with molecular markers for nuclear compartments, a transcription assay with 5'-fluorouridine, and in situ hybridization for telomeric DNA. TDP-43 is concentrated in euchromatin domains, specifically in perichromatin fibrils, nuclear sites of transcription and cotranscriptional splicing. In these structures, TDP-43 colocalizes with 5'-fluorouridine incorporation sites into nascent pre-mRNA. TDP-43 is absent in transcriptionally silent centromeric and telomeric heterochromatin, as well as in the Cajal body, a transcription free nuclear compartment. Furthermore, a weak TDP-43 immunolabeling is found in nuclear speckles of splicing factors. The specific localization of TDP-43 in active sites of transcription and cotranscriptional splicing is consistent with biochemical data indicating a role of TDP-43 in the regulation of transcription and alternative splicing.
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PMID:TDP-43 localizes in mRNA transcription and processing sites in mammalian neurons. 1953 30

Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitinated inclusions (FTLD-U) are major neurodegenerative diseases with TDP-43 pathology. Here we investigated the effects of methylene blue (MB) and dimebon, two compounds that have been reported to be beneficial in phase II clinical trials of Alzheimer's disease (AD), on the formation of TDP-43 aggregates in SH-SY5Y cells. Following treatment with 0.05 microM MB or 5 microM dimebon, the number of TDP-43 aggregates was reduced by 50% and 45%, respectively. The combined use of MB and dimebon resulted in a 80% reduction in the number. These findings were confirmed by immunoblot analysis. The results indicate that MB and dimebon may be useful for the treatment of ALS, FTLD-U and other TDP-43 proteinopathies.
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PMID:Methylene blue and dimebon inhibit aggregation of TDP-43 in cellular models. 1956 Apr 62

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

TAR DNA binding protein (TDP-43) mislocalization has been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS). We have recently reported that TDP-43 and PGRN expression is altered in response to axotomy in C57BL6 mice and that normal expression is restored following recovery. We have performed axotomies in two different presymptomatic models of motor neuron degeneration, low molecular weight neurofilament knockout (NFL(-/-)) mice and mutant SOD1(G93A) transgenic (mtSOD1(G93A)) mice aged 6 weeks, and observed TDP-43 and PGRN expression patterns in axotomized spinal motor neurons over 28 days. In contrast to both C57BL6 mice and mtSOD1(G93A) mice, behavioural deficits in NFL(-/-) mice were sustained. We did not observe differences in TDP-43 or PGRN expression between C57BL6 mice and mtSOD1(G93A) mice throughout the observation period. However, compared to C57BL6 mice and mtSOD1(G93A) mice, NFL(-/-) mice exhibited late upregulation of cytosolic TDP-43 expression and persistent downregulation of neuronal PGRN expression accompanied by caspase 3 activation on post-injury day 28. By post-injury day 42, no cytosolic TDP-43-positive neurons remained in NFL(-/-) mice, suggesting that they had undergone apoptotic cell death. These findings suggest that whereas TDP-43 expression is normally upregulated transiently following axotomy, in the absence of NFL this response is delayed and associated with caspase 3 activation and neuronal death. These results further support that TDP-43 is involved in neurofilament mRNA metabolism and transport, and provide insight into the pathogenesis of motor neuron death in ALS in which NFL mRNA levels are selectively suppressed.
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PMID:Cytosolic TDP-43 expression following axotomy is associated with caspase 3 activation in NFL-/- mice: support for a role for TDP-43 in the physiological response to neuronal injury. 1961 16

TDP-43 is a nuclear protein involved in exon skipping and alternative splicing. Recently, TDP-43 has been identified as the pathological signature protein in frontotemporal lobar degeneration with ubiquitin-positive inclusions and in amyotrophic lateral sclerosis. In addition, TDP-43-positive inclusions are present in Parkinson disease, dementia with Lewy bodies, and 30% of Alzheimer disease cases. Pathological TDP-43 is redistributed from the nucleus to the cytoplasm, where it accumulates. An approximately 25-kDa C-terminal fragment of TDP-43 accumulates in affected brain regions, suggesting that it may be involved in the disease pathogenesis. Here, we show that overexpression of the 25-kDa C-terminal fragment is sufficient to cause the mislocalization and cytoplasmic accumulation of endogenous full-length TDP-43 in two different cell lines, thus recapitulating a key biochemical characteristic of TDP-43 proteinopathies. We also found that TDP-43 mislocalization is associated with a reduction in the low molecular mass neurofilament mRNA levels. Notably, we show that the autophagic system plays a role in TDP-43 metabolism. Specifically, we found that autophagy inhibition increases the accumulation of the C-terminal fragments of TDP-43, whereas inhibition of mTOR, a key protein kinase involved in autophagy regulation, reduces the 25-kDa C-terminal fragment accumulation and restores TDP-43 localization. Our results suggest that autophagy induction may be a valid therapeutic target for TDP-43 proteinopathies.
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PMID:Rapamycin rescues TDP-43 mislocalization and the associated low molecular mass neurofilament instability. 1965 85

All patients with sporadic amyotrophic lateral sclerosis (SALS) have TDP-43 inclusions in their motor neurons, suggesting this protein plays a major role in the disease. Coding mutations in the gene for TDP-43, TARDBP, have been found in only a few patients with SALS. However, the non-coding regulatory regions of TARDBP have not yet been examined in SALS. We therefore sequenced both coding and non-coding regions of TARDBP in 46 tissue-banked SALS brains (brain DNA was used to detect somatic mutations). Non-coding variants (in the promoter or intron 1) were detected in 16 patients (35%) and coding variants in 4 (9%). Two known promoter variants were found more frequently in SALS patients than in controls. Two other variants, found in one patient each but not in controls, have potential regulatory functions. In addition, a novel exon 2 change with predicted functional effects was found in one patient. In summary, variants in the promoter and other non-coding regions of TARDBP may disturb the regulation of this gene in some patients with SALS.
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PMID:Genetic variants in the promoter of TARDBP in sporadic amyotrophic lateral sclerosis. 1969 77

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

Recently, Nishihira et al. demonstrated the presence of two types of TDP-43 pathology in sporadic amyotrophic lateral sclerosis (ALS) (Acta Neuropathol 2008; 116: 169-182). Type 1 represents the TDP-43 distribution pattern observed in classic ALS, whereas type 2 shows the presence of TDP-43 inclusions in the frontotemporal cortex, hippocampal formation, neostriatum and substantia nigra and is significantly associated with dementia. However, ALS with pallido-nigro-luysian degeneration (PNLD) is very rare. We recently encountered a case of ALS with PNLD of 9 years duration, in which the patient received artificial respiratory support for 6 years. In our case, neuronal loss and TDP-43-positive neuronal cytoplasmic inclusions were found in the globus pallidus, substantia nigra and subthalamic nucleus. Neither neuronal loss nor TDP-43-immunoreactive inclusions were found in the frontotemporal cortex and hippocampus. These findings suggest that the pallido-nigro-luysian system is also involved in the disease process of ALS and that ALS with PNLD is different from ALS with dementia based on the distribution pattern of neuronal loss and TDP-43 accumulation.
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PMID:Sporadic amyotrophic lateral sclerosis with pallido-nigro-luysian degeneration: a TDP-43 immunohistochemical study. 1970 66


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