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)

Potentially causative missense variations in the ANG gene and a positive association with the synonymous rs11701-G substitution was detected mainly in Irish and Scottish ALS patients. We screened 262 Italian SOD1 negative ALS patients (250 sporadic) and 415 matched controls for sequence variations in the coding, 3'/5' UTR and 5' flanking (642 bp) regions of the ANG gene. We identified 53 sequence variations of which 46 new, 20 with a minor allele frequency (MAF) >or=0.01 and only three localised in the coding sequence, namely the missense I46V, identified in one patient and two controls, and the synonymous G86G and T97T corresponding to rs11701 and rs2228653. None of the detected SNPs or of their haplotypic combinations was significantly associated with ALS susceptibility or clinical features. In conclusion, we did not detect the association with rs11701-G or with any other newly detected variation in the ANG regulatory region. Furthermore we did not identify potentially causal mutations in the coding region.
 ...
PMID:Variations in the coding and regulatory sequences of the angiogenin (ANG) gene are not associated to ALS (amyotrophic lateral sclerosis) in the Italian population. 1746 71

Mutations in human angiogenin (hANG), an angiogenic member of the RNase A superfamily, have been recently reported in patients with amyotrophic lateral sclerosis (ALS), a progressive late-onset neurodegenerative disorder. However, very little is known about the expression and subcellular distribution of ANG in the nervous system or its role in differentiation. Here we report that mouse angiogenin-1 (mAng-1) is strongly expressed in the developing nervous system during mouse embryogenesis and neuroectodermal differentiation of pluripotent P19 embryonal carcinoma cells. mAng1 is strongly expressed in motor neurons (MNs) in the spinal cord and dorsal root ganglia as well as in post-mitotic MNs derived from P19 cells. We also show for the first time that ANG expression is in the growth cones and neurites. NCI 65828, an inhibitor of the ribonucleolytic activity of hANG, affected pathfinding by P19-derived neurons but not neuronal differentiation. Our findings clearly show that ANG plays an important role in neurite pathfinding and this has implications for ALS.
 ...
PMID:A new role for angiogenin in neurite growth and pathfinding: implications for amyotrophic lateral sclerosis. 1746 98

Amyotrophic lateral sclerosis (ALS) is a late onset neurodegenerative disorder affecting upper and lower motor neurons (MNs). The molecular mechanisms underlying ALS are poorly understood. Mutations in SOD1 is one of the known causes of ALS but occur only in a very small number of cases of ALS. Interestingly, mutations in human angiogenin (hANG), a member of the ribonuclease A (RNase A) superfamily known to be involved in neovascularization, have been recently reported in patients with ALS, but the effects of these mutations on MN differentiation and survival has not been investigated. We have used the well-characterized pluripotent P19 embryonal carcinoma (EC) cell culture model of neuro-ectodermal differentiation to study the effects of hANG-ALS variants on MN differentiation and survival. Here we report that P19 EC cells induced to differentiate in the presence of hANG and hANG-ALS-associated variants internalize the wild-type and variant proteins. The P19 EC cells differentiate to form neurons but the ability of the neurites to extend and make contacts with neighbouring neurites is compromised when treated with the hANG-ALS variants. In addition, hANG-ALS variants also have a cytotoxic effect on MNs leading to their degeneration. hANG was able to protect neurons from hypoxia-induced cell death, but the variants of hANG implicated in ALS lacked the neuroprotective activity. Our findings show that ANG plays an important role in neurite extension/pathfinding and survival providing a causal link between mutations in hANG and ALS.
 ...
PMID:Human angiogenin is a neuroprotective factor and amyotrophic lateral sclerosis associated angiogenin variants affect neurite extension/pathfinding and survival of motor neurons. 1791 83

Genetic variations in two hypoxia-inducible angiogenic genes, VEGF and ANG, have been linked with sporadic amyotrophic lateral sclerosis (SALS). Common variations in these genes may reduce the levels or functioning of their products. VEGF and ANG belong to a larger group of angiogenic genes that are up-regulated under hypoxic conditions. We hypothesized that common genetic variation across other members of this group may also predispose to sporadic ALS. To screen other hypoxia-inducible angiogenic genes for association with SALS, we selected 112 tagging single nucleotide polymorphisms (tgSNPs) that captured the common genetic variation across 16 VEGF-like and eight ANG-like hypoxia-inducible genes. Screening for association was performed in 270 Irish individuals with typical SALS and 272 ethnically matched unrelated controls. SNPs showing association in the Irish phase were genotyped in a replication sample of 281 Swedish sporadic ALS patients and 286 Swedish controls. Seven markers showed association in the Irish. The one modest replication signal observed in the Swedish replication sample, at rs3801158 in the gene inhibin beta A, was for the opposite allele vs. the Irish cohort. We failed to detect association of common variation across 24 candidate hypoxia-inducible angiogenic genes with SALS.
 ...
PMID:Screening of hypoxia-inducible genes in sporadic ALS. 1860 1

To clarify the genetic background of amyotrophic lateral sclerosis (ALS)/parkinsonism-dementia complex (PDC) of the Kii peninsula, Japan (Kii ALS/PDC), we performed extended mutation analyses of three patients with pathologically diagnosed Kii ALS/PDC. Direct sequencing analyses were performed in 19 genes, including ALS/frontotemporal lobar degeneration (FTLD)-related genes (SOD2, SOD3, ALS2/alsin, SMN1, PGRN, ANG, VEGF, VCP, VAPB, DCTN1, CHMP2B, and TARDBP or TDP-43), tauopathy-related gene (GSK3beta), and parkinsonism-related genes (alpha-synuclein, LRRK2, parkin, DJ-1, PINK1, and ATP13A2). Gene dosage analyses were conducted in screening of MAPT, alpha-synuclein, TDP-43 (or TARDBP), GSK3beta, and parkin. We found no mutation in the 19 genes. We found a homozygous nonsynonymous SNP (ALS2/alsin V368M) shared by all the three patients. Gene dosage was normal in MAPT, alpha-synuclein, TDP-43, GSK3beta, and parkin. The present findings, together with a previous negative study on MAPT and SOD1 mutation, further elucidated the lack of causative mutations in all exons, exon-intron boundaries, or some rearrangements of the reported major causative or susceptible genes related to ALS, FTLD, parkinsonism, synucleinopathy, TDP-43 proteinopathy, and tauopathy. However, the familial aggregation and lack of any environment factors suggest that Kii ALS/PDC is caused by other yet unidentified genetic factors.
 ...
PMID:Mutation analyses in amyotrophic lateral sclerosis/parkinsonism-dementia complex of the Kii peninsula, Japan. 1875 52

A K17I mutation in the ANG gene encoding angiogenin has been identified in a case that we previously published as ALS with neuronal intranuclear protein inclusions (Seilhean et al. in Acta Neuropathol 108:81-87, 2004). These inclusions were immunoreactive for smooth muscle alpha-actin but not for angiogenin. Moreover, they were not labeled by anti-TDP-43 antibodies, while numerous cytoplasmic inclusions immunoreactive for ubiquitin, p62 and TDP-43 were detected in both oligodendrocytes and neurons in various regions of the central nervous system. In addition, expression of smooth muscle alpha-actin was increased in the liver where severe steatosis was observed. This is the first neuropathological description of a case with an ANG mutation. Angiogenin is known to interact with actin. Like other proteins involved in ALS pathogenesis, such as senataxin, TDP-43 and FUS/TLS, it plays a role in RNA maturation.
 ...
PMID:Accumulation of TDP-43 and alpha-actin in an amyotrophic lateral sclerosis patient with the K17I ANG mutation. 1944 21

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder of upper and lower motorneurons, leading to death in 3 to 5 years. Respiratory insufficiency and hypoxemia are closely linked during the clinical course of ALS. Chronic respiratory insufficiency and hypoxemia generally occur late in the disease course but rapid episodes of intermittent hypoxemia followed by reoxygenation can occur early and insidiously. Two pathways are involved in the response to hypoxemia: (i) hypoxia inducible factor-1 (HIF-1) and VEGF/HIF-2 and an erythropoietin (EPO) mediated pathway, in response to prolonged hypoxemia; and (ii) nuclear factor kappa-B (NFkappa-B) during acute hypoxemia followed by reoxygenation episodes, inducing inflammatory mediators: interleukin-6 (IL-6), TNF-alpha, cyclo oxygenase-2 (COX-2) and prostaglandin E-2 (PGE-2). Our aim was to specify the role of the different functional pathways of response to hypoxemia in sporadic ALS patients, compared with neurological controls and according to the level of hypoxemia. We report the results of several studies of hypoxemic and/or inflammatory mediators in the cerebrospinal fluid (CSF) from ALS patients, according to their respiratory status, showing a selective defect of HIF-1 mediated angiogenic factors (VEGF and angiogenin [ANG]) during chronic hypoxia in sporadic ALS patients, compared to hypoxemic neurological controls; contrasting with an early activation of the NFkappa-B pathway since the isolated desaturation stage (IL-6, TNF-alpha, PGE-2, angiopoietin-2) in the same cohort of sporadic ALS patients. All these results are consistent with a selective impairment of the HIF-1 pathway during chronic hypoxemia in ALS patients. Inflammatory mediators were strongly elevated, since the early stage of the disease until chronic hypoxemia, suggesting a compensatory mechanism.
 ...
PMID:[Mechanisms of deregulated response to hypoxia in sporadic amyotrophic lateral sclerosis: a clinical study]. 1966 Jul 77

Human bone marrow stromal cells (BM-SCs) possess the potential to differentiate, self-renew, and produce diverse trophic/growth factors and are an excellent cell therapy tool for degenerative diseases. However, they exhibit different therapeutic efficacies, depending on the health status and age of the cell donor. Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive motor neuron death in the central nervous system. In this study, we isolated BM-SCs from 11 ALS patients and characterized their potential secretory capacity of neurotrophic factors. We identified significant reductions in the expression of Oct-4 and Nanog , and in the trophic factors ANG, FGF -2, HGF, IGF-1, PIGF, SDF-1alpha , TGF-beta, and VEGF, but not in BDNF or ECGF. Migration of ALS-SCs was reduced, although the cells expressed the same markers for human mesenchymal phenotypes. These data suggest that ALS-SCs have diminished capacity as trophic mediators and may have reduced beneficial effects in cell therapy.
 ...
PMID:Bone marrow-derived stromal cells from amyotrophic lateral sclerosis patients have diminished stem cell capacity. 2003 May 61

Amyotrophic lateral sclerosis (ALS) has its onset in middle age and is a progressive disorder characterized by degeneration of motor neurons of the primary motor cortex, brainstem and spinal cord. Most cases of ALS are sporadic, but about 10% are familial. Genes known to cause classic familial ALS (FALS) are superoxide dismutase 1 (SOD1), ANG encoding angiogenin, TARDP encoding transactive response (TAR) DNA-binding protein TDP-43 (ref. 4) and fused in sarcoma/translated in liposarcoma (FUS, also known as TLS). However, these genetic defects occur in only about 20-30% of cases of FALS, and most genes causing FALS are unknown. Here we show that there are mutations in the gene encoding optineurin (OPTN), earlier reported to be a causative gene of primary open-angle glaucoma (POAG), in patients with ALS. We found three types of mutation of OPTN: a homozygous deletion of exon 5, a homozygous Q398X nonsense mutation and a heterozygous E478G missense mutation within its ubiquitin-binding domain. Analysis of cell transfection showed that the nonsense and missense mutations of OPTN abolished the inhibition of activation of nuclear factor kappa B (NF-kappaB), and the E478G mutation revealed a cytoplasmic distribution different from that of the wild type or a POAG mutation. A case with the E478G mutation showed OPTN-immunoreactive cytoplasmic inclusions. Furthermore, TDP-43- or SOD1-positive inclusions of sporadic and SOD1 cases of ALS were also noticeably immunolabelled by anti-OPTN antibodies. Our findings strongly suggest that OPTN is involved in the pathogenesis of ALS. They also indicate that NF-kappaB inhibitors could be used to treat ALS and that transgenic mice bearing various mutations of OPTN will be relevant in developing new drugs for this disorder.
 ...
PMID:Mutations of optineurin in amyotrophic lateral sclerosis. 2042 14

The cause of familial amyotrophic lateral sclerosis (FALS) has been attributed to mutations in several genes. The authors analyzed these genes, including SOD1, FUS, VAPB, ANG, TDP-43, FIG4, and CHMP2B, in a cohort of 15 index patients of Han Chinese descent with adult-onset FALS. Seven different mutations in eight patients, including three in SOD1 (G85R, T137R, and G138E), two in exon 15 of FUS (H517D and R521H), and two in exon 6 of TARDBP (M337V and N378D) were identified. Among them, T137R SOD1, G138E SOD1, H517D FUS, and N378D TARDBP were novel. No mutation was found in VAPB, ANG, FIG4, or CHMP2B genes. Mutations in SOD1, FUS, and TARDBP account for 20%, 13.3%, and 20% of FALS, respectively. This study defined the distribution and frequency of mutations of FALS in a Taiwanese Han Chinese population, which not only broadens the spectrum of the mutations causing FALS, but also further highlights the importance of FUS and TARDBP in the pathogenesis of amyotrophic lateral sclerosis (ALS).
 ...
PMID:FUS, TARDBP, and SOD1 mutations in a Taiwanese cohort with familial ALS. 2047 25


1 2 3 4 Next >>