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)

Oxidative stress is proposed to play a central role in the pathogenesis of amyotrophic lateral sclerosis (ALS). Anti-oxidant enzymes and DNA repair proteins are two major mechanisms by which cells counteract the deleterious effects of reactive oxygen species (ROS). Neurons may be particularly vulnerable to ROS-induced oxidative DNA damage; this is repaired by the base-excision repair (BER) pathway. Frontal cortical levels and activity of the pivotal BER protein apurinic/apyrimidinic endonuclease (APE) were determined in 11 patients with sporadic ALS and six age-matched control subjects. APE levels (p < 0.003) and activity (p < 0.000007) were significantly lower in ALS subjects than in controls. These findings suggest that ALS brain tissue is inefficient in repairing oxidative DNA damage.
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PMID:Evidence of reduced DNA repair in amyotrophic lateral sclerosis brain tissue. 917 31

We analyzed genomic DNA from ALS patients for mutations in the apurinic/apyrimidinic endonuclease (APEX nuclease) gene. We identified three rare polymorphisms in the untranslated region of the gene and one common two-allele polymorphism (D148E). The allelic frequency D148E was significantly different in sporadic ALS patients compared with controls. A conserved amino acid change and a 4-base pair deletion were also identified in sporadic ALS patients. These data suggest that APEX nuclease may contribute to the etiology of ALS.
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PMID:Molecular genetic analysis of the APEX nuclease gene in amyotrophic lateral sclerosis. 1037 43

DNA extracted from CNS tissue of 84 patients was screened by single-stranded conformation polymorphism (SSCP) and heteroduplex analysis for mutations in the apurinic/apyrimidinic endonuclease (APE) gene. One mutation was identified and characterized as a 4bp deletion in the 3'UTR. A rare polymorphism was identified in exon 3 and a common polymorphism in the coding region of exon 5. These results suggest that APE mutations do not account for a large number of ALS cases.
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PMID:Screening of AP endonuclease as a candidate gene for amyotrophic lateral sclerosis (ALS). 1085 27

Motor neurons degenerate in amyotrophic lateral sclerosis (ALS). The mechanisms for this neuronal cell death are not known, although apoptosis has been implicated. Oxidative damage to DNA and activation of p53 has been identified directly in motor neurons in cases of ALS. We evaluated whether motor neuron degeneration in ALS is associated with changes in the levels and function of the multifunctional protein apurinic/apyrimidinic endonuclease (APE/Ref-1). APE/Ref-1 functions as an enzyme in the DNA base-excision repair pathway and as a redox-regulation protein for transcription factors. The protein level and localization of APE/Ref-1 are changed in ALS. Immunoblotting showed that APE/Ref-1 protein levels are increased in selectively vulnerable central nervous system (CNS) regions in individuals with ALS compared to age-matched controls. Plasmid DNA repair assay demonstrated that APE from individuals with ALS is competent in repairing apurinic (AP) sites. DNA repair function in nuclear fractions is increased significantly in ALS motor cortex and spinal cord. Immunocytochemistry and single-cell densitometry revealed that APE/Ref-1 is expressed at lower levels in control motor neurons than in ALS motor neurons, which are decreased in number by 42% in motor cortex. APE/Ref-1 is increased in the nucleus of remaining upper motor neurons in ALS, which show a 38% loss of nuclear area. APE-Ref-1 is also upregulated in astrocytes in spinal cord white matter pathways in familial ALS. We conclude that mechanisms for DNA repair are activated in ALS, supporting the possibility that DNA damage is an upstream mechanism for motor neuron degeneration in this disease.
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PMID:DNA base-excision repair enzyme apurinic/apyrimidinic endonuclease/redox factor-1 is increased and competent in the brain and spinal cord of individuals with amyotrophic lateral sclerosis. 1223 Mar 4

Impairments in DNA repair enzymes have been observed in amyotrophic lateral sclerosis (ALS) tissues, particularly in the activity of the apurinic/apyrimidinic endonuclease 1 (APEX1). Moreover, it was suggested that the common APEX1 Asp148Glu polymorphism might be associated with ALS risk. To further address this question we performed the present study aimed at evaluating the contribution of the APEX1 Asp148Glu polymorphism in sporadic ALS (sALS) risk and clinical presentation, including age and site of onset and disease progression. We screened 134 sALS Italian patients and 129 matched controls for the presence of the APEX1 Asp148Glu polymorphism. No difference in APEX1 Asp148Glu allele and genotype frequencies was found between the groups, nor was the polymorphism associated with age and site of onset or disease progression. Present results do not support a role for the APEX1 Asp148Glu polymorphism in sALS pathogenesis in the Italian population.
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PMID:Lack of association between the APEX1 Asp148Glu polymorphism and sporadic amyotrophic lateral sclerosis. 1848 81

Glutamate is the most abundant excitatory neurotransmitter in the vertebrate central nervous system and plays an important role in synaptic plasticity required for learning and memory. Activation of glutamate ionotropic receptors promptly triggers membrane depolarization and Ca(2+) influx, resulting in the activation of several different protein kinases and transcription factors. For example, glutamate-mediated Ca(2+) influx activates Ca(2+)/calmodulin-dependent kinase, protein kinase C, and mitogen activated protein kinases resulting in activation of transcription factors such as cyclic AMP response element binding protein (CREB). Abnormally prolonged exposure to glutamate causes neuronal injury, and such "excitotoxicity" has been implicated in many acute and chronic diseases including ischemic stroke, epilepsy, amyotrophic lateral sclerosis, Alzheimer's, Huntington's and Parkinson's diseases. Interestingly, although glutamate-induced Ca(2+) influx can cause DNA damage by a mitochondrial reactive oxygen species-mediated mechanism, the Ca(2+) simultaneously activates CREB, resulting in up-regulation of the DNA repair and redox protein apurinic/apyrimidinic endonuclease 1. Here, we review connections between physiological or aberrant glutamate receptor activation, Ca(2+)-mediated signaling, oxidative DNA damage and repair efficiency, and neuronal vulnerability. We conclude that glutamate signaling involves an adaptive cellular stress response pathway that enhances DNA repair capability, thereby protecting neurons against injury and disease.
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PMID:The excitatory neurotransmitter glutamate stimulates DNA repair to increase neuronal resiliency. 2172 15