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)

Nervous system tissues from a number of patients with idiopathic neurological disorders were examined for biochemical evidence of RNA tumor virus infection. RNase-sensitive DNA polymerase activity was found in a cytoplasmic particulate fraction from two patients with Guamanian amyotrophic lateral sclerosis (ALS) but not in brains from two normal U.S. individuals. The buoyant density of the enzyme-containing fraction was 1.16-1.18 g/ml and could be converted to a denser region of the gradient (1.24 g/ml) by treatment with the nonionic surfactant, Sterox. The cation and detergent requirements for the endogenous RNase-sensitive DNA polymerase reaction were determined. The early (5 min) endogenous reverse transcriptase product was analyzed by cesium sulfate gradient centrifugation. RNase- and heat-sensitive RNA-DNA hybrids were detected in the product analysis of two ALS, one Parkinsonism-dementia (PD) brain, and two brains from asymptomatic Chamorros but not in brains from normal U.S. individuals and a number of patients with neuro-psychiatric disorders. The DNA product was a 4.5S heteropolymer that hybridized more extensively to RNA extracted from the enzyme-containing pellet from PD brain as compared to a similar fraction from normal U.S. brain. The DNA product appeared to be unrelated to Rausvher or visna virus 70S RNA as determined by RNA-[-3H]DNA hybridization.
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PMID:RNA-instructed DNA polymerase activity in a cytoplasmic particulate fraction in brains from Guamanian patients. 4 90

These studies were designed to determine if RIDP was present in a particulate fraction of brains from patients with ALS and PD. Evidence that we have detected RIDP is as follows: (a) DNA polymerase activity persists in the presence of concentrations of actinomycin D and distamycin that inhibit most DNA-directed DNA synthesis (25); (b) the majority of endogenous DNA polymerase activity is sensitive to prior treatment with RNase; (c) the early reaction product is a 4-5 S DNA heteropolymer joined by hydrogen bonds to an RNA molecule; and (d) the purified [3H]DNA product anneals to RNA extracted from the enzyme-containing pellet more extensively than to normal brain RNA or poly(rA). The enzyme activity is in a cytoplasmic particle that can be sedimented at high speed and has the buoyant density of RNA tumor viruses (1.16-1.18 gm/ml). This particulate fraction is not disrupted by physical manipulation and maintains its characteristic density with repeated centrifugations. Treatment with the nonionic surfactant Sterox changes the buoyant density of the enzyme-containing particle to 1.24 gm/ml, the density of the onconavirus virion core. Synthesis of RNA-DNA hybrids by an endogenous reverse transcriptase reaction was found only in normal and diseased Chamorro brains. Examination of a limited number of normal and diseased brains from individuals who lived in the United States produced negative results (39). Definitive characterization of this polymerase activity and identification as a true viral polymerase will depend on purification of biochemically active quantities of this polymerase to determine its template specificities, its cation preference, the fidelity of its transcription product, as well as its antigenic relationship to animal virus and human leukemic RIDP. Of critical importance in these studies will be differentiation of this activity from normal brain DNA polymerase gamma and terminal deoxynucleotidyltransferase.
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PMID:RNA tumor viruses as causative agents of chronic neurological disease. 6 87

To characterize neuronal gene expression in amyotrophic lateral sclerosis (ALS), we quantitated one glial and three neuronal mRNAs in spinal cords of 7 subjects with ALS and 11 controls. The ALS cases showed no loss of mRNA for the neurofilament light subunit when assessed with in situ hybridization. Northern analysis, and RNase protection assay; and no loss of mRNA for amyloid precursor protein or a growth-associated protein (GAP-43/B-50) on Northern analysis. ALS cords also showed no significant change in glial mRNA. Our findings indicate that expression of these neuronal mRNAs is well maintained in ALS-afflicted spinal cord. They do not support the hypothesis of a generalized impairment of neuronal gene transcription in the pathogenesis of this disorder.
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PMID:Neuronal gene expression in amyotrophic lateral sclerosis. 215 97

Neurofilament (NF) aggregates in motor neurons are a key neuropathological feature of amyotrophic lateral sclerosis (ALS). We have previously observed an alteration in the stoichiometry of NF subunit steady state mRNA levels in ALS spinal motor neurons using in situ hybridization and proposed that this led to aggregate formation. We have now examined the levels of NF mRNA in whole tissue homogenates of spinal cord using the RNase protection assay and real time reverse transcriptase-PCR and observed significant elevations of NF mRNA level in ALS. Compared with age-matched control, we observed a greater stability of heterogeneously expressed NFL mRNA in the presence of ALS spinal cord homogenates. Heat denaturing or protease K digestion of the control homogenates increased the stability of the NFL mRNA to levels observed in ALS homogenate. Increased NFL mRNA stability was also induced by increasing the percentage of ALS homogenate in an admixture of control and ALS homogenates. These observations suggest the presence of trans-acting NFL mRNA-destabilizing elements in control but not in ALS spinal cord homogenates. This was confirmed in gel retardation assays. We also observed that the destabilizing elements interact with the 3'-untranslated region of NFL mRNA. These findings suggest that the trans-acting NFL-destabilizing elements are selectively suppressed in ALS homogenates, resulting in an increased stability and level of NFL mRNA.
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PMID:Selective loss of trans-acting instability determinants of neurofilament mRNA in amyotrophic lateral sclerosis spinal cord. 1273 Feb 11

The ubiquitin-proteasome system (UPS) is a central component in the cellular defence against potentially toxic protein aggregates. UPS dysfunction is linked to the pathogenesis of both sporadic and inherited neurodegenerative diseases, including dominantly inherited familial amyotrophic lateral sclerosis (fALS). To investigate the role of the UPS in fALS pathogenesis, transgenic mice expressing mutant G9 3A Cu,Zn superoxide dismutase (SOD1) were crossed with transgenic mice expressing epitope tagged, wild-type or dominant-negative mutant ubiquitin (Ub(K48R)). RNase protection assays were used to confirm expression of the Ub transgenes in spinal cord and ubiquitin transgene levels were estimated to account for 9-12% of total ubiquitin. Mice expressing the G9 3A transgene exhibited neurological symptoms and histopathological changes typical of this model irrespective of ubiquitin transgene status. Impaired rotarod performance was observed in all G9 3A transgenics by 7 weeks of age irrespective of ubiquitin genotype. The presence of wild-type or mutant ubiquitin transgenes resulted in a small but significant delay in the onset of clinical symptoms and mild acceleration of disease progression, without influencing overall survival. These data suggest that relatively small changes in ubiquitin expression can influence the development of neurodegenerative disease and are consistent with a neuroprotective role for the UPS.
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PMID:Effect of ubiquitin expression on neuropathogenesis in a mouse model of familial amyotrophic lateral sclerosis. 1563 28

RNA interference has become the tool of choice to analyse the loss-of-function of individual genes and has been exploited to identify complex regulatory pathways following genomic screening. RNAi has both admirers and detractors, but is undeniably a technique with great potential, which has come a long way in the short time since its discovery. RNAi utilises cellular machinery associated with the processing of naturally occurring micro RNA (miRNAs). Effective use of RNAi requires detailed knowledge of the individual steps and the proteins involved, as well as the similarities and distinctions between miRNA and siRNA pathways. RNAi was originally induced by the introduction of long double stranded RNAs (dsRNAs) into cells in which the RNA was cleaved into short RNAs which effectively interfered with a transcription of cognate mRNA. More recently an introduction of short approximately 22 nucleotide RNA duplexes has become the standard in short-term experiments, but is insufficient for long-term knock-down assays. Long-term expression of siRNAs has been achieved by in vivo transcription from plasmids coding for short hairpin RNAs (shRNAs). The cellular processing of shRNAs shares common features with the biogenesis of naturally occurring miRNA such as cleavage by nuclear RNase Drosha, export from the nucleus, processing by a cytoplasmic RNase Dicer, and incorporation into the RNA-induced silencing complex (RISC). Each step has a crucial influence on the efficiency of RNAi and their consideration should be a part of a standard experimental design. RNAi has moved from a purely experimental technique to the stage of potential clinical applications. The possible use of RNAi in the treatment of spinocerebellar ataxia or amyotrophic lateral sclerosis, with its advantages and pitfalls and possible extensions to other diseases are discussed.
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PMID:Design of shRNAs for RNAi-A lesson from pre-miRNA processing: possible clinical applications. 1632 11

Down-regulation of vascular endothelial growth factor (VEGF) in the mouse leads to progressive and selective degeneration of motor neurons similar to amyotrophic lateral sclerosis (ALS). In mice expressing ALS-associated mutant superoxide dismutase 1 (SOD1), VEGF mRNA expression in the spinal cord declines significantly prior to the onset of clinical manifestations. In vitro models suggest that dysregulation of VEGF mRNA stability contributes to that decline. Here, we show that the major RNA stabilizer, Hu Antigen R (HuR), and TIA-1-related protein (TIAR) colocalize with mutant SOD1 in mouse spinal cord extracts and cultured glioma cells. The colocalization was markedly reduced or abolished by RNase treatment. Immunoanalysis of transfected cells indicated that colocalization occurred in insoluble aggregates and inclusions. RNA immunoprecipitation showed a significant loss of VEGF mRNA binding to HuR and TIAR in mutant SOD1 cells, and there was marked depletion of HuR from polysomes. Ectopic expression of HuR in mutant SOD1 cells more than doubled the mRNA half-life of VEGF and significantly increased expression to that of wild-type SOD1 control. Cellular effects produced by mutant SOD1, including impaired mitochondrial function and oxidative stress-induced apoptosis, were reversed by HuR in a gene dose-dependent pattern. In summary, our findings indicate that mutant SOD1 impairs post-transcriptional regulation by sequestering key regulatory RNA-binding proteins. The rescue effect of HuR suggests that this impairment, whether related to VEGF or other potential mRNA targets, contributes to cytotoxicity in ALS.
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PMID:Amyotrophic lateral sclerosis-linked mutant SOD1 sequesters Hu antigen R (HuR) and TIA-1-related protein (TIAR): implications for impaired post-transcriptional regulation of vascular endothelial growth factor. 1980 46

Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disorder affecting motoneurons. Mutations in angiogenin, encoding a member of the pancreatic RNase A superfamily, segregate with ALS. We previously demonstrated that angiogenin administration shows promise as a neuroprotective therapeutic in studies using transgenic ALS mice and primary motoneuron cultures. Its mechanism of action and target cells in the spinal cord, however, are largely unknown. Using mixed motoneuron cultures, motoneuron-like NSC34 cells, and primary astroglia cultures as model systems, we here demonstrate that angiogenin is a neuronally secreted factor that is endocytosed by astroglia and mediates neuroprotection in paracrine. We show that wild-type angiogenin acts unidirectionally to induce RNA cleavage in astroglia, while the ALS-associated K40I mutant is also secreted and endocytosed, but fails to induce RNA cleavage. Angiogenin uptake into astroglia requires heparan sulfate proteoglycans, and engages clathrin-mediated endocytosis. We show that this uptake mechanism exists for mouse and human angiogenin, and delivers a functional RNase output. Moreover, we identify syndecan 4 as the angiogenin receptor mediating the selective uptake of angiogenin into astroglia. Our data provide new insights into the paracrine activities of angiogenin in the nervous system, and further highlight the critical role of non-neuronal cells in the pathogenesis of ALS.
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PMID:Motoneurons secrete angiogenin to induce RNA cleavage in astroglia. 2249 49

Mutations in angiogenin (ANG), a member of the ribonuclease A superfamily, are associated with amyotrophic lateral sclerosis (ALS; sporadic and familial) and Parkinson's disease. We have previously shown that ANG is expressed in neurons during neuro-ectodermal differentiation, and that it has both neurotrophic and neuroprotective functions. Here we report the atomic resolution structure of native ANG and 11 ANG-ALS variants. We correlate the structural changes to the effects on neuronal survival and the ability to induce stress granules in neuronal cell lines. ANG-ALS variants that affect the structure of the catalytic site and either decrease or increase the RNase activity affect neuronal survival. Neuronal cell lines expressing the ANG-ALS variants also lack the ability to form stress granules. Our structure-function studies on these ANG-ALS variants are the first to provide insights into the cellular and molecular mechanisms underlying their role in ALS.
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PMID:Structural and molecular insights into the mechanism of action of human angiogenin-ALS variants in neurons. 2304 79

Phosphorylated and truncated TAR DNA-binding protein-43 (TDP-43) is a major component of ubiquitinated cytoplasmic inclusions in neuronal and glial cells of two TDP-43 proteinopathies, amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Modifications of TDP-43 are thus considered to play an important role in the pathogenesis of TDP-43 proteinopathies. However, both the initial cause of these abnormal modifications and the TDP-43 region responsible for its aggregation remain uncertain. Here we report that the 32 kDa C-terminal fragment of TDP-43, which lacks the RNP2 motif of RNA binding motif 1 (RRM1), formed aggregates in cultured cells, and that similar phenotypes were obtained when the RNP2 motif was either deleted from or mutated in full-length TDP-43. These aggregations were ubiquitinated, phosphorylated and truncated, and sequestered the 25 kDa C-terminal TDP-43 fragment seen in the neurons of TDP-43 proteinopathy patients. In addition, incubation with RNase decreased the solubility of TDP-43 in cell lysates. These findings suggest that the RNP2 motif of RRM1 plays a substantial role in pathological TDP-43 modifications and that it is possible that disruption of RNA binding may underlie the process of TDP-43 aggregation.
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PMID:RNP2 of RNA recognition motif 1 plays a central role in the aberrant modification of TDP-43. 2384 May 65


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