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  1. Gabriel N Valbuena, Milena Rizzardini, Sara Cimini, Alexandros P Siskos, Caterina Bendotti, Lavinia Cantoni and Hector C Keun.
    Metabolomic Analysis Reveals Increased Aerobic Glycolysis and Amino Acid Deficit in a Cellular Model of Amyotrophic Lateral Sclerosis.. Molecular neurobiology 53(4):2222–40, May 2016.
    Abstract Defects in energy metabolism are potential pathogenic mechanisms in amyotrophic lateral sclerosis (ALS), a rapidly fatal disease with no cure. The mechanisms through which this occurs remain elusive and their understanding may prove therapeutically useful. We used metabolomics and stable isotope tracers to examine metabolic changes in a well-characterized cell model of familial ALS, the motor neuronal NSC-34 line stably expressing human wild-type Cu/Zn superoxide dismutase (wtSOD1) or mutant G93A (G93ASOD1). Our findings indicate that wt and G93ASOD1 expression both enhanced glucose metabolism under serum deprivation. However, in wtSOD1 cells, this phenotype increased supply of amino acids for protein and glutathione synthesis, while in G93ASOD1 cells it was associated with death, aerobic glycolysis, and a broad dysregulation of amino acid homeostasis. Aerobic glycolysis was mainly due to induction of pyruvate dehydrogenase kinase 1. Our study thus provides novel insight into the role of deranged energy metabolism as a cause of poor adaptation to stress and a promoter of neural cell damage in the presence of mutant SOD1. Furthermore, the metabolic alterations we report may help explain why mitochondrial dysfunction and impairment of the endoplasmic reticulum stress response are frequently seen in ALS.
    URL, DOI BibTeX

    @article{Valbuena2016,
    	abstract = "Defects in energy metabolism are potential pathogenic mechanisms in amyotrophic lateral sclerosis (ALS), a rapidly fatal disease with no cure. The mechanisms through which this occurs remain elusive and their understanding may prove therapeutically useful. We used metabolomics and stable isotope tracers to examine metabolic changes in a well-characterized cell model of familial ALS, the motor neuronal NSC-34 line stably expressing human wild-type Cu/Zn superoxide dismutase (wtSOD1) or mutant G93A (G93ASOD1). Our findings indicate that wt and G93ASOD1 expression both enhanced glucose metabolism under serum deprivation. However, in wtSOD1 cells, this phenotype increased supply of amino acids for protein and glutathione synthesis, while in G93ASOD1 cells it was associated with death, aerobic glycolysis, and a broad dysregulation of amino acid homeostasis. Aerobic glycolysis was mainly due to induction of pyruvate dehydrogenase kinase 1. Our study thus provides novel insight into the role of deranged energy metabolism as a cause of poor adaptation to stress and a promoter of neural cell damage in the presence of mutant SOD1. Furthermore, the metabolic alterations we report may help explain why mitochondrial dysfunction and impairment of the endoplasmic reticulum stress response are frequently seen in ALS.",
    	author = "Valbuena, Gabriel N and Rizzardini, Milena and Cimini, Sara and Siskos, Alexandros P and Bendotti, Caterina and Cantoni, Lavinia and Keun, Hector C",
    	doi = "10.1007/s12035-015-9165-7",
    	file = ":C$\backslash$:/Users/riku/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Valbuena et al. - 2016 - Metabolomic Analysis Reveals Increased Aerobic Glycolysis and Amino Acid Deficit in a Cellular Model of Amyotro.pdf:pdf",
    	issn = "1559-1182",
    	journal = "Molecular neurobiology",
    	month = "may",
    	number = 4,
    	pages = "2222--40",
    	pmid = 25963727,
    	title = "{Metabolomic Analysis Reveals Increased Aerobic Glycolysis and Amino Acid Deficit in a Cellular Model of Amyotrophic Lateral Sclerosis.}",
    	url = "http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=4823370\&tool=pmcentrez\&rendertype=abstract",
    	volume = 53,
    	year = 2016
    }
    
  2. Sara Cimini, Milena Rizzardini, Gloria Biella and Lavinia Cantoni.
    Hypoxia causes autophagic stress and derangement of metabolic adaptation in a cell model of amyotrophic lateral sclerosis.. Journal of neurochemistry 129(3):413–25, 2014.
    Abstract Amyotrophic lateral sclerosis is a fatal neurodegenerative disease that affects motor neurons. The recruitment of autophagy (macroautophagy) and mitochondrial dysfunction are documented in amyotrophic lateral sclerosis patients and experimental models expressing mutant forms of Cu, Zn superoxide dismutase (SOD1) protein, but their impact in the disease remains unclear. Hypoxia is a stress closely related to the disease in patients and mutant SOD1 mice; in individual cells, hypoxia activates autophagy and regulates mitochondrial metabolism as fundamental adaptive mechanisms. Our aim was to examine whether mutant SOD1 changed this response. Hypoxia (1% O2 for 22 h) caused greater loss of viability and more marked activation of caspase 3/7 in the motor neuronal NSC-34 cell line stably transfected with the G93A mutant human SOD1 (G93A-NSC) than in the one with the wild-type SOD1 (WT-NSC) or in untransfected NSC-34. In the G93A-NSC cells, there was a more marked accumulation of the LC3-II autophagy protein, attributable to autophagic stress; 3-methyladenine, which acts on initiation of autophagy, fully rescued G93A-NSC viability and reduced the activation of caspase 3/7 indicating this was a secondary event; the metabolic handling of hypoxia was inappropriate possibly contributing to the autophagic stress. Our findings evidentiate that the G93A mutation of SOD1 profoundly altered the adaptive metabolic response to hypoxia and this could increase the cell susceptibility to this stress. Hypoxia activates autophagy and modifies glycolysis and mitochondrial respiration as fundamental cell adaptive mechanisms. This stress is closely related to amyotrophic lateral sclerosis. The recruitment of autophagy and mitochondrial dysfunction are documented in patients and models expressing mutant Cu, Zn superoxide dismutase (SOD1) protein, but their impact in the disease remains unclear. G93ASOD1 cells were more susceptible to hypoxia than wild-type SOD1 cells and showed autophagic stress and inappropriate handling of energy metabolism. Defective adaptation to hypoxia may contribute to neurodegeneration.
    URL, DOI BibTeX

    @article{Cimini2014,
    	abstract = "Amyotrophic lateral sclerosis is a fatal neurodegenerative disease that affects motor neurons. The recruitment of autophagy (macroautophagy) and mitochondrial dysfunction are documented in amyotrophic lateral sclerosis patients and experimental models expressing mutant forms of Cu, Zn superoxide dismutase (SOD1) protein, but their impact in the disease remains unclear. Hypoxia is a stress closely related to the disease in patients and mutant SOD1 mice; in individual cells, hypoxia activates autophagy and regulates mitochondrial metabolism as fundamental adaptive mechanisms. Our aim was to examine whether mutant SOD1 changed this response. Hypoxia (1\% O2 for 22 h) caused greater loss of viability and more marked activation of caspase 3/7 in the motor neuronal NSC-34 cell line stably transfected with the G93A mutant human SOD1 (G93A-NSC) than in the one with the wild-type SOD1 (WT-NSC) or in untransfected NSC-34. In the G93A-NSC cells, there was a more marked accumulation of the LC3-II autophagy protein, attributable to autophagic stress; 3-methyladenine, which acts on initiation of autophagy, fully rescued G93A-NSC viability and reduced the activation of caspase 3/7 indicating this was a secondary event; the metabolic handling of hypoxia was inappropriate possibly contributing to the autophagic stress. Our findings evidentiate that the G93A mutation of SOD1 profoundly altered the adaptive metabolic response to hypoxia and this could increase the cell susceptibility to this stress. Hypoxia activates autophagy and modifies glycolysis and mitochondrial respiration as fundamental cell adaptive mechanisms. This stress is closely related to amyotrophic lateral sclerosis. The recruitment of autophagy and mitochondrial dysfunction are documented in patients and models expressing mutant Cu, Zn superoxide dismutase (SOD1) protein, but their impact in the disease remains unclear. G93ASOD1 cells were more susceptible to hypoxia than wild-type SOD1 cells and showed autophagic stress and inappropriate handling of energy metabolism. Defective adaptation to hypoxia may contribute to neurodegeneration.",
    	author = "Cimini, Sara and Rizzardini, Milena and Biella, Gloria and Cantoni, Lavinia",
    	doi = "10.1111/jnc.12642",
    	issn = "1471-4159",
    	journal = "Journal of neurochemistry",
    	month = "",
    	number = 3,
    	pages = "413--25",
    	pmid = 24359187,
    	title = "{Hypoxia causes autophagic stress and derangement of metabolic adaptation in a cell model of amyotrophic lateral sclerosis.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/24359187",
    	volume = 129,
    	year = 2014
    }
    
  3. Scott P Allen, Sandeep Rajan, Lynn Duffy, Heather Mortiboys, Adrian Higginbottom, Andrew J Grierson and Pamela J Shaw.
    Superoxide dismutase 1 mutation in a cellular model of amyotrophic lateral sclerosis shifts energy generation from oxidative phosphorylation to glycolysis.. Neurobiology of aging 35(6):1499–509, 2014.
    Abstract Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder involving the progressive degeneration of motor neurons in the brain and spinal cord. Mitochondrial dysfunction plays a key role in ALS disease progression and has been observed in several ALS cellular and animal models. Here, we show that fibroblasts isolated from ALS cases with a Cu/Zn superoxide dismutase (SOD1) I113T mutation recapitulate these mitochondrial defects. Using a novel technique, which measures mitochondrial respiration and glycolytic flux simultaneously in living cells, we have shown that SOD1 mutation causes a reduction in mitochondrial respiration and an increase in glycolytic flux. This causes a reduction in adenosine triphosphate produced by oxidative phosphorylation and an increase in adenosine triphosphate produced by glycolysis. Switching the energy source from glucose to galactose caused uncoupling of mitochondria with increased proton leak in SOD1(I113T) fibroblasts. Assessment of the contribution of fatty acid oxidation to total respiration, suggested that fatty acid oxidation is reduced in SOD1 ALS fibroblasts, an effect which can be mimicked by starving the control cells of glucose. These results highlight the importance of understanding the interplay between the major metabolic pathways, which has the potential to lead to strategies to correct the metabolic dysregulation observed in ALS cases.
    URL, DOI BibTeX

    @article{Allen2014,
    	abstract = "Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder involving the progressive degeneration of motor neurons in the brain and spinal cord. Mitochondrial dysfunction plays a key role in ALS disease progression and has been observed in several ALS cellular and animal models. Here, we show that fibroblasts isolated from ALS cases with a Cu/Zn superoxide dismutase (SOD1) I113T mutation recapitulate these mitochondrial defects. Using a novel technique, which measures mitochondrial respiration and glycolytic flux simultaneously in living cells, we have shown that SOD1 mutation causes a reduction in mitochondrial respiration and an increase in glycolytic flux. This causes a reduction in adenosine triphosphate produced by oxidative phosphorylation and an increase in adenosine triphosphate produced by glycolysis. Switching the energy source from glucose to galactose caused uncoupling of mitochondria with increased proton leak in SOD1(I113T) fibroblasts. Assessment of the contribution of fatty acid oxidation to total respiration, suggested that fatty acid oxidation is reduced in SOD1 ALS fibroblasts, an effect which can be mimicked by starving the control cells of glucose. These results highlight the importance of understanding the interplay between the major metabolic pathways, which has the potential to lead to strategies to correct the metabolic dysregulation observed in ALS cases.",
    	author = "Allen, Scott P and Rajan, Sandeep and Duffy, Lynn and Mortiboys, Heather and Higginbottom, Adrian and Grierson, Andrew J and Shaw, Pamela J",
    	doi = "10.1016/j.neurobiolaging.2013.11.025",
    	issn = "1558-1497",
    	journal = "Neurobiology of aging",
    	month = "",
    	number = 6,
    	pages = "1499--509",
    	pmid = 24439480,
    	title = "{Superoxide dismutase 1 mutation in a cellular model of amyotrophic lateral sclerosis shifts energy generation from oxidative phosphorylation to glycolysis.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/24439480",
    	volume = 35,
    	year = 2014
    }
    
  4. Aiman S Saab, Iva D Tzvetanova and Klaus-Armin Nave.
    The role of myelin and oligodendrocytes in axonal energy metabolism.. Current opinion in neurobiology 23(6):1065–72, 2013.
    Abstract In vertebrates, the myelination of long axons by oligodendrocytes and Schwann cells enables rapid impulse propagation. However, myelin sheaths are not only passive insulators. Oligodendrocytes are also known to support axonal functions and long-term integrity. Some of the underlying mechanisms have now been identified. It could be shown that oligodendrocytes can survive in vivo by aerobic glycolysis. Myelinating oligodendrocytes release lactate through the monocarboxylate transporter MCT1. Lactate is then utilized by axons for mitochondrial ATP generation. Studying axo-glial signalling and energy metabolism will lead to a better understanding of neurodegenerative diseases, in which axonal energy metabolism fails. These include neurological disorders as diverse as multiple sclerosis, leukodystrophies, and amyotrophic lateral sclerosis.
    URL, DOI BibTeX

    @article{Saab2013,
    	abstract = "In vertebrates, the myelination of long axons by oligodendrocytes and Schwann cells enables rapid impulse propagation. However, myelin sheaths are not only passive insulators. Oligodendrocytes are also known to support axonal functions and long-term integrity. Some of the underlying mechanisms have now been identified. It could be shown that oligodendrocytes can survive in vivo by aerobic glycolysis. Myelinating oligodendrocytes release lactate through the monocarboxylate transporter MCT1. Lactate is then utilized by axons for mitochondrial ATP generation. Studying axo-glial signalling and energy metabolism will lead to a better understanding of neurodegenerative diseases, in which axonal energy metabolism fails. These include neurological disorders as diverse as multiple sclerosis, leukodystrophies, and amyotrophic lateral sclerosis.",
    	author = "Saab, Aiman S and Tzvetanova, Iva D and Nave, Klaus-Armin",
    	doi = "10.1016/j.conb.2013.09.008",
    	issn = "1873-6882",
    	journal = "Current opinion in neurobiology",
    	month = "",
    	number = 6,
    	pages = "1065--72",
    	pmid = 24094633,
    	title = "{The role of myelin and oligodendrocytes in axonal energy metabolism.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/24094633",
    	volume = 23,
    	year = 2013
    }
    
  5. Katie Richardson, Scott P Allen, Heather Mortiboys, Andrew J Grierson, Stephen B Wharton, Paul G Ince, Pamela J Shaw and Paul R Heath.
    The effect of SOD1 mutation on cellular bioenergetic profile and viability in response to oxidative stress and influence of mutation-type.. PloS one 8(6):e68256, January 2013.
    Abstract Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disorder characterized by the progressive degeneration of motor neurons. Substantial evidence implicates oxidative stress and mitochondrial dysfunction as early events in disease progression. Our aim was to ascertain whether mutation of the SOD1 protein increases metabolic functional susceptibility to oxidative stress. Here we used a motor neuron-like cell line (NSC34) stably transfected with various human mutant SOD1 transgenes (G93A, G37R, H48Q) to investigate the impact of oxidative stress on cell viability and metabolic function within intact cells. NSC34 cells expressing mutant SOD1 showed a dose dependent reduction in cell viability when exposed to oxidative stress induced by hydrogen peroxide, with variation between mutations. The G93A transfectants showed greater cell death and LDH release compared to cells transfected with the other SOD1 mutations, and H48Q showed an accelerated decline at later time points. Differences in mitochondrial bioenergetics, including mitochondrial respiration, coupling efficiency and proton leak, were identified between the mutations, consistent with the differences observed in viability. NSC34 cells expressing G93A SOD1 displayed reduced coupled respiration and mitochondrial membrane potential compared to controls. Furthermore, the G93A mutation had significantly increased metabolic susceptibility to oxidative stress, with hydrogen peroxide increasing ROS production, reducing both cellular oxygen consumption and glycolytic flux in the cell. This study highlights bioenergetic defects within a cellular model of ALS and suggests that oxidative stress is not only detrimental to oxygen consumption but also glycolytic flux, which could lead to an energy deficit in the cell.
    URL, DOI BibTeX

    @article{Richardson2013,
    	abstract = "Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disorder characterized by the progressive degeneration of motor neurons. Substantial evidence implicates oxidative stress and mitochondrial dysfunction as early events in disease progression. Our aim was to ascertain whether mutation of the SOD1 protein increases metabolic functional susceptibility to oxidative stress. Here we used a motor neuron-like cell line (NSC34) stably transfected with various human mutant SOD1 transgenes (G93A, G37R, H48Q) to investigate the impact of oxidative stress on cell viability and metabolic function within intact cells. NSC34 cells expressing mutant SOD1 showed a dose dependent reduction in cell viability when exposed to oxidative stress induced by hydrogen peroxide, with variation between mutations. The G93A transfectants showed greater cell death and LDH release compared to cells transfected with the other SOD1 mutations, and H48Q showed an accelerated decline at later time points. Differences in mitochondrial bioenergetics, including mitochondrial respiration, coupling efficiency and proton leak, were identified between the mutations, consistent with the differences observed in viability. NSC34 cells expressing G93A SOD1 displayed reduced coupled respiration and mitochondrial membrane potential compared to controls. Furthermore, the G93A mutation had significantly increased metabolic susceptibility to oxidative stress, with hydrogen peroxide increasing ROS production, reducing both cellular oxygen consumption and glycolytic flux in the cell. This study highlights bioenergetic defects within a cellular model of ALS and suggests that oxidative stress is not only detrimental to oxygen consumption but also glycolytic flux, which could lead to an energy deficit in the cell.",
    	author = "Richardson, Katie and Allen, Scott P and Mortiboys, Heather and Grierson, Andrew J and Wharton, Stephen B and Ince, Paul G and Shaw, Pamela J and Heath, Paul R",
    	doi = "10.1371/journal.pone.0068256",
    	file = ":C$\backslash$:/Users/riku/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Richardson et al. - 2013 - The effect of SOD1 mutation on cellular bioenergetic profile and viability in response to oxidative stress an.pdf:pdf",
    	issn = "1932-6203",
    	journal = "PloS one",
    	keywords = "Animals,Cell Death,Cell Death: drug effects,Cell Death: genetics,Cell Line,Cell Respiration,Cell Respiration: drug effects,Cell Respiration: genetics,Cell Survival,Cell Survival: drug effects,Cell Survival: genetics,Energy Metabolism,Energy Metabolism: drug effects,Energy Metabolism: genetics,Glycolysis,Glycolysis: drug effects,Glycolysis: genetics,Humans,Hydrogen Peroxide,Hydrogen Peroxide: pharmacology,Mice,Motor Neurons,Motor Neurons: drug effects,Motor Neurons: metabolism,Mutation,Mutation: drug effects,Mutation: genetics,Oxidative Stress,Oxidative Stress: drug effects,Oxidative Stress: genetics,Oxygen Consumption,Oxygen Consumption: drug effects,Oxygen Consumption: genetics,Reactive Oxygen Species,Reactive Oxygen Species: metabolism,Superoxide Dismutase,Superoxide Dismutase: genetics,Superoxide Dismutase: metabolism",
    	month = "jan",
    	number = 6,
    	pages = "e68256",
    	pmid = 23840839,
    	title = "{The effect of SOD1 mutation on cellular bioenergetic profile and viability in response to oxidative stress and influence of mutation-type.}",
    	url = "http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3695905\&tool=pmcentrez\&rendertype=abstract",
    	volume = 8,
    	year = 2013
    }
    
  6. Seiko Ishida, Pénélope Andreux, Carole Poitry-Yamate, Johan Auwerx and Douglas Hanahan.
    Bioavailable copper modulates oxidative phosphorylation and growth of tumors.. Proceedings of the National Academy of Sciences of the United States of America 110(48):19507–12, 2013.
    Abstract Copper is an essential trace element, the imbalances of which are associated with various pathological conditions, including cancer, albeit via largely undefined molecular and cellular mechanisms. Here we provide evidence that levels of bioavailable copper modulate tumor growth. Chronic exposure to elevated levels of copper in drinking water, corresponding to the maximum allowed in public water supplies, stimulated proliferation of cancer cells and de novo pancreatic tumor growth in mice. Conversely, reducing systemic copper levels with a chelating drug, clinically used to treat copper disorders, impaired both. Under such copper limitation, tumors displayed decreased activity of the copper-binding mitochondrial enzyme cytochrome c oxidase and reduced ATP levels, despite enhanced glycolysis, which was not accompanied by increased invasiveness of tumors. The antiproliferative effect of copper chelation was enhanced when combined with inhibitors of glycolysis. Interestingly, larger tumors contained less copper than smaller tumors and exhibited comparatively lower activity of cytochrome c oxidase and increased glucose uptake. These results establish copper as a tumor promoter and reveal that varying levels of copper serves to regulate oxidative phosphorylation in rapidly proliferating cancer cells inside solid tumors. Thus, activation of glycolysis in tumors may in part reflect insufficient copper bioavailability in the tumor microenvironment.
    URL, DOI BibTeX

    @article{Ishida2013,
    	abstract = "Copper is an essential trace element, the imbalances of which are associated with various pathological conditions, including cancer, albeit via largely undefined molecular and cellular mechanisms. Here we provide evidence that levels of bioavailable copper modulate tumor growth. Chronic exposure to elevated levels of copper in drinking water, corresponding to the maximum allowed in public water supplies, stimulated proliferation of cancer cells and de novo pancreatic tumor growth in mice. Conversely, reducing systemic copper levels with a chelating drug, clinically used to treat copper disorders, impaired both. Under such copper limitation, tumors displayed decreased activity of the copper-binding mitochondrial enzyme cytochrome c oxidase and reduced ATP levels, despite enhanced glycolysis, which was not accompanied by increased invasiveness of tumors. The antiproliferative effect of copper chelation was enhanced when combined with inhibitors of glycolysis. Interestingly, larger tumors contained less copper than smaller tumors and exhibited comparatively lower activity of cytochrome c oxidase and increased glucose uptake. These results establish copper as a tumor promoter and reveal that varying levels of copper serves to regulate oxidative phosphorylation in rapidly proliferating cancer cells inside solid tumors. Thus, activation of glycolysis in tumors may in part reflect insufficient copper bioavailability in the tumor microenvironment.",
    	author = "Ishida, Seiko and Andreux, P\'{e}n\'{e}lope and Poitry-Yamate, Carole and Auwerx, Johan and Hanahan, Douglas",
    	doi = "10.1073/pnas.1318431110",
    	file = ":C$\backslash$:/Users/riku/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Ishida et al. - 2013 - Bioavailable copper modulates oxidative phosphorylation and growth of tumors.pdf:pdf",
    	issn = "1091-6490",
    	journal = "Proceedings of the National Academy of Sciences of the United States of America",
    	keywords = "Adenosine Triphosphate,Adenosine Triphosphate: metabolism,Animals,Biological Availability,Blotting, Western,Copper,Copper: toxicity,DNA Primers,DNA Primers: genetics,Drinking Water,Drinking Water: analysis,Energy Metabolism,Energy Metabolism: drug effects,Glycolysis,Glycolysis: physiology,Membrane Potential, Mitochondrial,Membrane Potential, Mitochondrial: drug effects,Mice,Neoplasms,Neoplasms: physiopathology,Oxidative Phosphorylation,Oxidative Phosphorylation: drug effects,Positron-Emission Tomography,Real-Time Polymerase Chain Reaction,Respiration,Tumor Microenvironment,Tumor Microenvironment: physiology,Water Pollutants, Chemical,Water Pollutants, Chemical: toxicity",
    	month = "",
    	number = 48,
    	pages = "19507--12",
    	pmid = 24218578,
    	title = "{Bioavailable copper modulates oxidative phosphorylation and growth of tumors.}",
    	url = "http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3845132\&tool=pmcentrez\&rendertype=abstract",
    	volume = 110,
    	year = 2013
    }
    
  7. Mariana Machado Lauer, Camila Bento Oliveira, Natalia Lie Inocencio Yano and Adalto Bianchini.
    Copper effects on key metabolic enzymes and mitochondrial membrane potential in gills of the estuarine crab Neohelice granulata at different salinities.. Comparative biochemistry and physiology. Toxicology & pharmacology : CBP 156(3-4):140–7, November 2012.
    Abstract The estuarine crab Neohelice granulata was exposed (96 h) to a sublethal copper concentration under two different physiological conditions (hyperosmoregulating crabs: 2 ppt salinity, 1 mg Cu/L; isosmotic crabs: 30 ppt salinity, 5 mg Cu/L). After exposure, gills (anterior and posterior) were dissected and activities of enzymes involved in glycolysis (hexokinase, phosphofructokinase, pyruvate kinase, lactate dehydrogenase), Krebs cycle (citrate synthase), and mitochondrial electron transport chain (cytochrome c oxidase) were analyzed. Membrane potential of mitochondria isolated from anterior and posterior gill cells was also evaluated. In anterior gills of crabs acclimated to 2 ppt salinity, copper exposure inhibited hexokinase, phosphofructokinase, pyruvate kinase, and citrate synthase activity, increased lactate dehydrogenase activity, and reduced the mitochondrial membrane potential. In posterior gills, copper inhibited hexokinase and pyruvate kinase activity, and increased citrate synthase activity. In anterior gills of crabs acclimated to 30 ppt salinity, copper exposure inhibited phosphofructokinase and citrate synthase activity, and increased hexokinase activity. In posterior gills, copper inhibited phosphofructokinase and pyruvate kinase activity, and increased hexokinase and lactate dehydrogenase activity. Copper did not affect cytochrome c oxidase activity in either anterior or posterior gills of crabs acclimated to 2 and 30 ppt salinity. These findings indicate that exposure to a sublethal copper concentration affects the activity of enzymes involved in glycolysis and Krebs cycle, especially in anterior (respiratory) gills of hyperosmoregulating crabs. Changes observed indicate a switch from aerobic to anaerobic metabolism, characterizing a situation of functional hypoxia. In this case, reduced mitochondrial membrane potential would suggest a decrease in ATP production. Although gills of isosmotic crabs were also affected by copper exposure, changes observed suggest no impact in the overall tissue ATP production. Also, findings suggest that copper exposure would stimulate the pentose phosphate pathway to support the antioxidant system requirements. Although N. granulata is very tolerant to copper, acute exposure to this metal can disrupt the energy balance by affecting biochemical systems involved in carbohydrate metabolism.
    URL, DOI BibTeX

    @article{Lauer2012,
    	abstract = "The estuarine crab Neohelice granulata was exposed (96 h) to a sublethal copper concentration under two different physiological conditions (hyperosmoregulating crabs: 2 ppt salinity, 1 mg Cu/L; isosmotic crabs: 30 ppt salinity, 5 mg Cu/L). After exposure, gills (anterior and posterior) were dissected and activities of enzymes involved in glycolysis (hexokinase, phosphofructokinase, pyruvate kinase, lactate dehydrogenase), Krebs cycle (citrate synthase), and mitochondrial electron transport chain (cytochrome c oxidase) were analyzed. Membrane potential of mitochondria isolated from anterior and posterior gill cells was also evaluated. In anterior gills of crabs acclimated to 2 ppt salinity, copper exposure inhibited hexokinase, phosphofructokinase, pyruvate kinase, and citrate synthase activity, increased lactate dehydrogenase activity, and reduced the mitochondrial membrane potential. In posterior gills, copper inhibited hexokinase and pyruvate kinase activity, and increased citrate synthase activity. In anterior gills of crabs acclimated to 30 ppt salinity, copper exposure inhibited phosphofructokinase and citrate synthase activity, and increased hexokinase activity. In posterior gills, copper inhibited phosphofructokinase and pyruvate kinase activity, and increased hexokinase and lactate dehydrogenase activity. Copper did not affect cytochrome c oxidase activity in either anterior or posterior gills of crabs acclimated to 2 and 30 ppt salinity. These findings indicate that exposure to a sublethal copper concentration affects the activity of enzymes involved in glycolysis and Krebs cycle, especially in anterior (respiratory) gills of hyperosmoregulating crabs. Changes observed indicate a switch from aerobic to anaerobic metabolism, characterizing a situation of functional hypoxia. In this case, reduced mitochondrial membrane potential would suggest a decrease in ATP production. Although gills of isosmotic crabs were also affected by copper exposure, changes observed suggest no impact in the overall tissue ATP production. Also, findings suggest that copper exposure would stimulate the pentose phosphate pathway to support the antioxidant system requirements. Although N. granulata is very tolerant to copper, acute exposure to this metal can disrupt the energy balance by affecting biochemical systems involved in carbohydrate metabolism.",
    	author = "Lauer, Mariana Machado and de Oliveira, Camila Bento and Yano, Natalia Lie Inocencio and Bianchini, Adalto",
    	doi = "10.1016/j.cbpc.2012.08.001",
    	issn = "1532-0456",
    	journal = "Comparative biochemistry and physiology. Toxicology \& pharmacology : CBP",
    	keywords = "Acclimatization,Animals,Brachyura,Brachyura: drug effects,Brachyura: enzymology,Carbohydrate Metabolism,Carbohydrate Metabolism: drug effects,Citrate (si)-Synthase,Citrate (si)-Synthase: antagonists \& inhibitors,Citrate (si)-Synthase: metabolism,Citric Acid Cycle,Copper,Copper: adverse effects,Environmental Exposure,Environmental Exposure: adverse effects,Enzyme Activation,Enzyme Inhibitors,Enzyme Inhibitors: adverse effects,Gills,Gills: drug effects,Gills: enzymology,Glycolysis,L-Lactate Dehydrogenase,L-Lactate Dehydrogenase: metabolism,Membrane Potential, Mitochondrial,Mitochondria,Mitochondria: metabolism,Phosphofructokinases,Phosphofructokinases: antagonists \& inhibitors,Phosphofructokinases: metabolism,Pyruvate Kinase,Pyruvate Kinase: antagonists \& inhibitors,Pyruvate Kinase: metabolism,Salinity,Water Pollutants, Chemical,Water Pollutants, Chemical: adverse effects,Water-Electrolyte Balance",
    	month = "nov",
    	number = "3-4",
    	pages = "140--7",
    	pmid = 22892099,
    	title = "{Copper effects on key metabolic enzymes and mitochondrial membrane potential in gills of the estuarine crab Neohelice granulata at different salinities.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/22892099",
    	volume = 156,
    	year = 2012
    }
    
  8. Irfana Muqbil, Frances W J Beck, Bin Bao, Fazlul H Sarkar, Ramzi M Mohammad, S M Hadi and Asfar S Azmi.
    Old wine in a new bottle: the Warburg effect and anticancer mechanisms of resveratrol.. Current pharmaceutical design 18(12):1645–54, January 2012.
    Abstract Resveratrol found in fruits, vegetables and beverages such as red wine, has been extensively evaluated for its anticardiovascular disease and cancer preventive effects. Even though studies have demonstrated its anti-tumor effects, there is still no clear explanation for cancer cell selective mechanisms of action of resveratrol. Initial investigations were focused on its anti-oxidant and cytoprotective mechanism of action, yet, a large number of studies have demonstrated that resveratrol can behave either as anti-oxidant or pro-oxidant depending on the selective microenvironment. What makes resveratrol a protective agent in normal cells and a radical generator possessing cytotoxic activity against cancer cells is a widely debated topic. There must be certain conditions found in tumors that allow resveratrol to become a pro-oxidant that clearly differs from that found in normal cells. Results of studies from our group have established that many different dietary agents can mobilize intracellular copper ions and in the process, generate reactive oxygen species through Fenton type reactions leading to oxidative DNA breakage and consequently, cell death. More significantly, we demonstrated that such pro-oxidant-induced DNA damage and apoptotic activity are enhanced in low pH environments; characteristically observed in tumors due to preferential dependence on glycolysis or the "Warburg effect". This review discusses the recent advancements in understanding the pro-oxidant anti-cancer behavior of resveratrol as a dietary chemopreventive agent, explained in the light of the Warburg effect.
    URL BibTeX

    @article{Muqbil2012,
    	abstract = {Resveratrol found in fruits, vegetables and beverages such as red wine, has been extensively evaluated for its anticardiovascular disease and cancer preventive effects. Even though studies have demonstrated its anti-tumor effects, there is still no clear explanation for cancer cell selective mechanisms of action of resveratrol. Initial investigations were focused on its anti-oxidant and cytoprotective mechanism of action, yet, a large number of studies have demonstrated that resveratrol can behave either as anti-oxidant or pro-oxidant depending on the selective microenvironment. What makes resveratrol a protective agent in normal cells and a radical generator possessing cytotoxic activity against cancer cells is a widely debated topic. There must be certain conditions found in tumors that allow resveratrol to become a pro-oxidant that clearly differs from that found in normal cells. Results of studies from our group have established that many different dietary agents can mobilize intracellular copper ions and in the process, generate reactive oxygen species through Fenton type reactions leading to oxidative DNA breakage and consequently, cell death. More significantly, we demonstrated that such pro-oxidant-induced DNA damage and apoptotic activity are enhanced in low pH environments; characteristically observed in tumors due to preferential dependence on glycolysis or the "Warburg effect". This review discusses the recent advancements in understanding the pro-oxidant anti-cancer behavior of resveratrol as a dietary chemopreventive agent, explained in the light of the Warburg effect.},
    	author = "Muqbil, Irfana and Beck, Frances W J and Bao, Bin and Sarkar, Fazlul H and Mohammad, Ramzi M and Hadi, S M and Azmi, Asfar S",
    	issn = "1873-4286",
    	journal = "Current pharmaceutical design",
    	keywords = "Animals,Copper,Copper: metabolism,Glycolysis,Glycolysis: physiology,Humans,Hydrogen-Ion Concentration,Neoplasms,Neoplasms: drug therapy,Neoplasms: metabolism,Reactive Oxygen Species,Reactive Oxygen Species: pharmacology,Reactive Oxygen Species: therapeutic use,Stilbenes,Stilbenes: pharmacology,Stilbenes: therapeutic use",
    	month = "jan",
    	number = 12,
    	pages = "1645--54",
    	pmid = 22288443,
    	title = "{Old wine in a new bottle: the Warburg effect and anticancer mechanisms of resveratrol.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/22288443",
    	volume = 18,
    	year = 2012
    }
    
  9. Svitlana Garbuzova-Davis, Maria C O Rodrigues, Diana G Hernandez-Ontiveros, Michael K Louis, Alison E Willing, Cesario V Borlongan and Paul R Sanberg.
    Amyotrophic lateral sclerosis: a neurovascular disease.. Brain research 1398:113–25, June 2011.
    Abstract Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disease with a complicated pathogenesis. Compelling evidence indicates impairment of all neurovascular unit components including the blood-brain and blood-spinal cord barriers (BBB/BSCB) in both patients and animal models, leading to classification of ALS as a neurovascular disease. The present review provides an updated analysis of the normal and impaired BBB/BSCB, focusing on the ALS-altered barrier. Here we describe the roles of cellular components, tight junctions, transport systems, cell interactions, cytokines, matrix metalloproteinases, and free radicals in the BBB/BSCB disruption, along with recent evidence from experimental and clinical ALS studies. The BBB/BSCB is a promising research area in ALS and this review will reveal some aspects of microvascular pathology in ALS and hopefully provide ideas for the development of new therapeutic strategies.
    URL, DOI BibTeX

    @article{Garbuzova-Davis2011,
    	abstract = "Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disease with a complicated pathogenesis. Compelling evidence indicates impairment of all neurovascular unit components including the blood-brain and blood-spinal cord barriers (BBB/BSCB) in both patients and animal models, leading to classification of ALS as a neurovascular disease. The present review provides an updated analysis of the normal and impaired BBB/BSCB, focusing on the ALS-altered barrier. Here we describe the roles of cellular components, tight junctions, transport systems, cell interactions, cytokines, matrix metalloproteinases, and free radicals in the BBB/BSCB disruption, along with recent evidence from experimental and clinical ALS studies. The BBB/BSCB is a promising research area in ALS and this review will reveal some aspects of microvascular pathology in ALS and hopefully provide ideas for the development of new therapeutic strategies.",
    	author = "Garbuzova-Davis, Svitlana and Rodrigues, Maria C O and Hernandez-Ontiveros, Diana G and Louis, Michael K and Willing, Alison E and Borlongan, Cesario V and Sanberg, Paul R",
    	doi = "10.1016/j.brainres.2011.04.049",
    	file = ":C$\backslash$:/Users/riku/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Garbuzova-Davis et al. - 2011 - Amyotrophic lateral sclerosis a neurovascular disease.pdf:pdf",
    	issn = "1872-6240",
    	journal = "Brain research",
    	keywords = "Amyotrophic Lateral Sclerosis,Amyotrophic Lateral Sclerosis: metabolism,Amyotrophic Lateral Sclerosis: physiopathology,Animals,Blood-Brain Barrier,Blood-Brain Barrier: metabolism,Blood-Brain Barrier: pathology,Blood-Brain Barrier: physiopathology,Central Nervous System,Central Nervous System: blood supply,Central Nervous System: metabolism,Central Nervous System: physiopathology,Cerebral Arteries,Cerebral Arteries: metabolism,Cerebral Arteries: physiopathology,Humans",
    	month = "jun",
    	pages = "113--25",
    	pmid = 21632035,
    	title = "{Amyotrophic lateral sclerosis: a neurovascular disease.}",
    	url = "http://www.sciencedirect.com/science/article/pii/S0006899311008705",
    	volume = 1398,
    	year = 2011
    }
    
  10. Ivo F Scheiber and Ralf Dringen.
    Copper accelerates glycolytic flux in cultured astrocytes.. Neurochemical research 36(5):894–903, May 2011.
    Abstract Astrocyte-rich primary cultures were used to investigate the consequences of a copper exposure on the glucose metabolism of astrocytes. After application of CuCl(2) (30 $\mu$M) the specific cellular copper content increased from initial 1.5 ± 0.2 nmol/mg to a steady state level of 7.9 ± 0.9 nmol/mg within about 12 h. The copper accumulation was accompanied by a significant increase in the extracellular lactate concentration. The stimulating effect of copper on the lactate production remained after removal of extracellular copper. Copper treatment accelerated the rates of both glucose consumption and lactate production by about 60%. The copper induced acceleration of glycolytic flux was prevented by inhibition of protein synthesis, and additive to the stimulation of glycolysis observed for inhibitors of respiration or prolyl hydroxylases. A copper induced stimulation of glycolytic flux in astrocytes could have severe consequences for the glucose metabolism of the brain in conditions of copper overload.
    URL, DOI BibTeX

    @article{Scheiber2011,
    	abstract = "Astrocyte-rich primary cultures were used to investigate the consequences of a copper exposure on the glucose metabolism of astrocytes. After application of CuCl(2) (30 $\mu$M) the specific cellular copper content increased from initial 1.5 ± 0.2 nmol/mg to a steady state level of 7.9 ± 0.9 nmol/mg within about 12 h. The copper accumulation was accompanied by a significant increase in the extracellular lactate concentration. The stimulating effect of copper on the lactate production remained after removal of extracellular copper. Copper treatment accelerated the rates of both glucose consumption and lactate production by about 60\%. The copper induced acceleration of glycolytic flux was prevented by inhibition of protein synthesis, and additive to the stimulation of glycolysis observed for inhibitors of respiration or prolyl hydroxylases. A copper induced stimulation of glycolytic flux in astrocytes could have severe consequences for the glucose metabolism of the brain in conditions of copper overload.",
    	author = "Scheiber, Ivo F and Dringen, Ralf",
    	doi = "10.1007/s11064-011-0419-0",
    	issn = "1573-6903",
    	journal = "Neurochemical research",
    	keywords = "Animals,Astrocytes,Astrocytes: drug effects,Astrocytes: metabolism,Cells, Cultured,Copper,Copper: pharmacology,Cycloheximide,Cycloheximide: pharmacology,Electron Transport,Glycolysis,Lactic Acid,Lactic Acid: biosynthesis,Rats,Rats, Wistar",
    	month = "may",
    	number = 5,
    	pages = "894--903",
    	pmid = 21318477,
    	title = "{Copper accelerates glycolytic flux in cultured astrocytes.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/21318477",
    	volume = 36,
    	year = 2011
    }
    
  11. Anna Mart\'ınez, Manuel Portero-Otin, Reinald Pamplona and Isidre Ferrer.
    Protein targets of oxidative damage in human neurodegenerative diseases with abnormal protein aggregates.. Brain pathology (Zurich, Switzerland) 20(2):281–97, 2010.
    Abstract Human neurodegenerative diseases with abnormal protein aggregates are associated with aberrant post-translational modifications, solubility, aggregation and fibril formation of selected proteins which cannot be degraded by cytosolic proteases, ubiquitin-protesome system and autophagy, and, therefore, accumulate in cells and extracellular compartments as residual debris. In addition to the accumulation of "primary" proteins, several other mechanisms are involved in the degenerative process and probably may explain crucial aspects such as the timing, selective cellular vulnerability and progression of the disease in particular individuals. One of these mechanisms is oxidative stress, which occurs in the vast majority of, if not all, degenerative diseases of the nervous system. The present review covers most of the protein targets that have been recognized as modified proteins mainly using bidimensional gel electrophoresis, Western blotting with oxidative and nitrosative markers, and identified by mass spectrometry in Alzheimer disease; certain tauopathies such as progressive supranuclear palsy, Pick disease, argyrophilic grain disease and frontotemporal lobar degeneration linked to mutations in tau protein, for example, FTLD-tau, Parkinson disease and related alpha-synucleinopathies; Huntington disease; and amyotrophic lateral sclerosis, together with related animal and cellular models. Vulnerable proteins can be mostly grouped in defined metabolic pathways covering glycolysis and energy metabolism, cytoskeletal, chaperoning, cellular stress responses, and members of the ubiquitin-proteasome system. Available information points to the fact that vital metabolic pathways are hampered by protein oxidative damage in several human degenerative diseases and that oxidative damage occurs at very early stages of the disease. Yet parallel functional studies are limited and further work is needed to document whether protein oxidation results in loss of activity and impaired performance. A better understanding of proteins susceptible to oxidation and nitration may serve to define damaged metabolic networks at early stages of disease and to advance therapeutic interventions to attenuate disease progression.
    URL, DOI BibTeX

    @article{Martinez2010,
    	abstract = {Human neurodegenerative diseases with abnormal protein aggregates are associated with aberrant post-translational modifications, solubility, aggregation and fibril formation of selected proteins which cannot be degraded by cytosolic proteases, ubiquitin-protesome system and autophagy, and, therefore, accumulate in cells and extracellular compartments as residual debris. In addition to the accumulation of "primary" proteins, several other mechanisms are involved in the degenerative process and probably may explain crucial aspects such as the timing, selective cellular vulnerability and progression of the disease in particular individuals. One of these mechanisms is oxidative stress, which occurs in the vast majority of, if not all, degenerative diseases of the nervous system. The present review covers most of the protein targets that have been recognized as modified proteins mainly using bidimensional gel electrophoresis, Western blotting with oxidative and nitrosative markers, and identified by mass spectrometry in Alzheimer disease; certain tauopathies such as progressive supranuclear palsy, Pick disease, argyrophilic grain disease and frontotemporal lobar degeneration linked to mutations in tau protein, for example, FTLD-tau, Parkinson disease and related alpha-synucleinopathies; Huntington disease; and amyotrophic lateral sclerosis, together with related animal and cellular models. Vulnerable proteins can be mostly grouped in defined metabolic pathways covering glycolysis and energy metabolism, cytoskeletal, chaperoning, cellular stress responses, and members of the ubiquitin-proteasome system. Available information points to the fact that vital metabolic pathways are hampered by protein oxidative damage in several human degenerative diseases and that oxidative damage occurs at very early stages of the disease. Yet parallel functional studies are limited and further work is needed to document whether protein oxidation results in loss of activity and impaired performance. A better understanding of proteins susceptible to oxidation and nitration may serve to define damaged metabolic networks at early stages of disease and to advance therapeutic interventions to attenuate disease progression.},
    	author = "Mart\'{\i}nez, Anna and Portero-Otin, Manuel and Pamplona, Reinald and Ferrer, Isidre",
    	doi = "10.1111/j.1750-3639.2009.00326.x",
    	issn = "1750-3639",
    	journal = "Brain pathology (Zurich, Switzerland)",
    	keywords = "Animals,Humans,Neurodegenerative Diseases,Neurodegenerative Diseases: metabolism,Oxidative Stress,Oxidative Stress: physiology,Proteins,Proteins: metabolism",
    	month = "",
    	number = 2,
    	pages = "281--97",
    	pmid = 19725834,
    	title = "{Protein targets of oxidative damage in human neurodegenerative diseases with abnormal protein aggregates.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/19725834",
    	volume = 20,
    	year = 2010
    }
    
  12. K Vijayalakshmi, Phalguni Anand Alladi, T N Sathyaprabha, Jamuna R Subramaniam, A Nalini and T R Raju.
    Cerebrospinal fluid from sporadic amyotrophic lateral sclerosis patients induces degeneration of a cultured motor neuron cell line.. Brain research 1263:122–33, March 2009.
    Abstract We investigated the effect of Cerebrospinal Fluid (CSF) from sporadic Amyotrophic Lateral Sclerosis patients (SALS-CSF) on motor neuron-like cells to delineate the pathomechanism of SALS. Exposure of NSC-34 cells to SALS-CSF caused lower viability, reduction in differentiation and enhanced lactate dehydrogenase activity. Additionally, reduced choline acetyl transferase expression alongside intracellular aggregation of phosphorylated neurofilaments was prominently seen. The aggregates were immunopositive for ubiquitin. These findings are comparable to the pathological changes seen in the postmortem tissue of ALS patients. Unlimited supply of NSC-34 cells and their vulnerability to SALS-CSF render them to be a good bioassay system to identify new therapeutic agents conferring protection to motor neurons.
    URL, DOI BibTeX

    @article{Vijayalakshmi2009,
    	abstract = "We investigated the effect of Cerebrospinal Fluid (CSF) from sporadic Amyotrophic Lateral Sclerosis patients (SALS-CSF) on motor neuron-like cells to delineate the pathomechanism of SALS. Exposure of NSC-34 cells to SALS-CSF caused lower viability, reduction in differentiation and enhanced lactate dehydrogenase activity. Additionally, reduced choline acetyl transferase expression alongside intracellular aggregation of phosphorylated neurofilaments was prominently seen. The aggregates were immunopositive for ubiquitin. These findings are comparable to the pathological changes seen in the postmortem tissue of ALS patients. Unlimited supply of NSC-34 cells and their vulnerability to SALS-CSF render them to be a good bioassay system to identify new therapeutic agents conferring protection to motor neurons.",
    	author = "Vijayalakshmi, K and Alladi, Phalguni Anand and Sathyaprabha, T N and Subramaniam, Jamuna R and Nalini, A and Raju, T R",
    	doi = "10.1016/j.brainres.2009.01.041",
    	issn = "1872-6240",
    	journal = "Brain research",
    	keywords = "Amyotrophic Lateral Sclerosis,Amyotrophic Lateral Sclerosis: cerebrospinal fluid,Analysis of Variance,Animals,Blotting, Western,Cell Line, Tumor,Cell Survival,Cell Survival: physiology,Choline O-Acetyltransferase,Choline O-Acetyltransferase: metabolism,Cytoskeleton,Cytoskeleton: metabolism,Gene Expression,Glycolysis,Glycolysis: physiology,Humans,Mice,Microscopy, Confocal,Motor Neurons,Motor Neurons: pathology,Motor Neurons: physiology,Nerve Degeneration,Nerve Degeneration: physiopathology,Neurogenesis,Neurogenesis: physiology,Phosphorylation,Photomicrography,Ubiquitin,Ubiquitin: metabolism",
    	month = "mar",
    	pages = "122--33",
    	pmid = 19368830,
    	title = "{Cerebrospinal fluid from sporadic amyotrophic lateral sclerosis patients induces degeneration of a cultured motor neuron cell line.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/19368830",
    	volume = 1263,
    	year = 2009
    }
    
  13. Carsten W Lederer, Antonietta Torrisi, Maria Pantelidou, Niovi Santama and Sebastiano Cavallaro.
    Pathways and genes differentially expressed in the motor cortex of patients with sporadic amyotrophic lateral sclerosis.. BMC genomics 8:26, 2007.
    Abstract BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal disorder caused by the progressive degeneration of motoneurons in brain and spinal cord. Despite identification of disease-linked mutations, the diversity of processes involved and the ambiguity of their relative importance in ALS pathogenesis still represent a major impediment to disease models as a basis for effective therapies. Moreover, the human motor cortex, although critical to ALS pathology and physiologically altered in most forms of the disease, has not been screened systematically for therapeutic targets. RESULTS: By whole-genome expression profiling and stringent significance tests we identify genes and gene groups de-regulated in the motor cortex of patients with sporadic ALS, and interpret the role of individual candidate genes in a framework of differentially expressed pathways. Our findings emphasize the importance of defense responses and cytoskeletal, mitochondrial and proteasomal dysfunction, reflect reduced neuronal maintenance and vesicle trafficking, and implicate impaired ion homeostasis and glycolysis in ALS pathogenesis. Additionally, we compared our dataset with publicly available data for the SALS spinal cord, and show a high correlation of changes linked to the diseased state in the SALS motor cortex. In an analogous comparison with data for the Alzheimer's disease hippocampus we demonstrate a low correlation of global changes and a moderate correlation for changes specifically linked to the SALS diseased state. CONCLUSION: Gene and sample numbers investigated allow pathway- and gene-based analyses by established error-correction methods, drawing a molecular portrait of the ALS motor cortex that faithfully represents many known disease features and uncovers several novel aspects of ALS pathology. Contrary to expectations for a tissue under oxidative stress, nuclear-encoded mitochondrial genes are uniformly down-regulated. Moreover, the down-regulation of mitochondrial and glycolytic genes implies a combined reduction of mitochondrial and cytoplasmic energy supply, with a possible role in the death of ALS motoneurons. Identifying candidate genes exclusively expressed in non-neuronal cells, we also highlight the importance of these cells in disease development in the motor cortex. Notably, some pathways and candidate genes identified by this study are direct or indirect targets of medication already applied to unrelated illnesses and point the way towards the rapid development of effective symptomatic ALS therapies.
    URL, DOI BibTeX

    @article{Lederer2007,
    	abstract = "BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal disorder caused by the progressive degeneration of motoneurons in brain and spinal cord. Despite identification of disease-linked mutations, the diversity of processes involved and the ambiguity of their relative importance in ALS pathogenesis still represent a major impediment to disease models as a basis for effective therapies. Moreover, the human motor cortex, although critical to ALS pathology and physiologically altered in most forms of the disease, has not been screened systematically for therapeutic targets. RESULTS: By whole-genome expression profiling and stringent significance tests we identify genes and gene groups de-regulated in the motor cortex of patients with sporadic ALS, and interpret the role of individual candidate genes in a framework of differentially expressed pathways. Our findings emphasize the importance of defense responses and cytoskeletal, mitochondrial and proteasomal dysfunction, reflect reduced neuronal maintenance and vesicle trafficking, and implicate impaired ion homeostasis and glycolysis in ALS pathogenesis. Additionally, we compared our dataset with publicly available data for the SALS spinal cord, and show a high correlation of changes linked to the diseased state in the SALS motor cortex. In an analogous comparison with data for the Alzheimer's disease hippocampus we demonstrate a low correlation of global changes and a moderate correlation for changes specifically linked to the SALS diseased state. CONCLUSION: Gene and sample numbers investigated allow pathway- and gene-based analyses by established error-correction methods, drawing a molecular portrait of the ALS motor cortex that faithfully represents many known disease features and uncovers several novel aspects of ALS pathology. Contrary to expectations for a tissue under oxidative stress, nuclear-encoded mitochondrial genes are uniformly down-regulated. Moreover, the down-regulation of mitochondrial and glycolytic genes implies a combined reduction of mitochondrial and cytoplasmic energy supply, with a possible role in the death of ALS motoneurons. Identifying candidate genes exclusively expressed in non-neuronal cells, we also highlight the importance of these cells in disease development in the motor cortex. Notably, some pathways and candidate genes identified by this study are direct or indirect targets of medication already applied to unrelated illnesses and point the way towards the rapid development of effective symptomatic ALS therapies.",
    	author = "Lederer, Carsten W and Torrisi, Antonietta and Pantelidou, Maria and Santama, Niovi and Cavallaro, Sebastiano",
    	doi = "10.1186/1471-2164-8-26",
    	file = ":C$\backslash$:/Users/riku/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Lederer et al. - 2007 - Pathways and genes differentially expressed in the motor cortex of patients with sporadic amyotrophic lateral sc.pdf:pdf",
    	issn = "1471-2164",
    	journal = "BMC genomics",
    	keywords = "Aged,Aged, 80 and over,Alzheimer Disease,Alzheimer Disease: metabolism,Amyotrophic Lateral Sclerosis,Amyotrophic Lateral Sclerosis: genetics,Amyotrophic Lateral Sclerosis: metabolism,Female,Gene Expression Profiling,Hippocampus,Hippocampus: metabolism,Humans,Male,Middle Aged,Models, Biological,Molecular Sequence Data,Motor Cortex,Motor Cortex: metabolism,Reverse Transcriptase Polymerase Chain Reaction,Signal Transduction,Spinal Cord,Spinal Cord: metabolism",
    	month = "",
    	pages = 26,
    	pmid = 17244347,
    	title = "{Pathways and genes differentially expressed in the motor cortex of patients with sporadic amyotrophic lateral sclerosis.}",
    	url = "http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1796866\&tool=pmcentrez\&rendertype=abstract",
    	volume = 8,
    	year = 2007
    }
    
  14. Fiona M Menzies, Mark R Cookson, Robert W Taylor, Douglass M Turnbull, Zofia M A Chrzanowska-Lightowlers, Lichun Dong, Denise A Figlewicz and Pamela J Shaw.
    Mitochondrial dysfunction in a cell culture model of familial amyotrophic lateral sclerosis.. Brain : a journal of neurology 125(Pt 7):1522–33, 2002.
    Abstract The molecular mechanisms by which mutations in the gene for Cu/Zn superoxide dismutase (SOD1) lead to the selective death of motor neurones in familial amyotrophic lateral sclerosis (FALS) remain incompletely understood. Previous evidence has indicated that mitochondrial abnormalities may develop during motor neurone injury, but several important questions remain unanswered. We have developed a cell culture model of FALS in which a motor neurone cell line (NSC34) has been stably transfected to express normal or mutant human SOD1 at levels approximating to those seen in the human disease. The aims of the study were to: (i) investigate whether morphological mitochondrial abnormalities occur at expression levels of mutant SOD1 close to physiological levels; and (ii) determine whether the presence of mutant SOD1 causes abnormalities of mitochondrial respiratory chain function and changes in cellular bioenergetic parameters in motor neuronal cells. Using this cellular model, we demonstrate that the presence of mutant SOD1 results in the development of abnormally swollen and pale staining mitochondria. These morphological changes are accompanied by biochemical abnormalities with specific decreases in the activities of complexes II and IV of the mitochondrial electron transfer chain. These same complexes are inhibited when control NSC34 cells are subjected to oxidative stress induced by serum withdrawal. The decrease in respiratory chain complex activity in the presence of mutant SOD1 was not accompanied by decreased expression of representative proteins present in these complexes. Motor neuronal cells expressing mutant SOD1 showed increased cell death when exposed to oxidative stress by serum withdrawal, whereas the presence of normal human SOD1 exerted a protective effect. Under basal, unstressed culture conditions, no change in the ATP : ADP ratio was observed in the presence of mutant SOD1. However, the mitochondrial changes associated with the presence of mutant SOD1 clearly had adverse cellular bioenergetic consequences as shown by increased cell death in the presence of pharmacological inhibition of the glycolytic pathway. We conclude that one important mechanism by which mutant SOD1 causes motor neurone injury involves inhibition of specific components of the mitochondrial electron transfer chain. Therapeutic measures aimed at protecting mitochondrial respiratory chain function may be useful in SOD1 related familial and possibly other forms of amyotrophic lateral sclerosis.
    URL BibTeX

    @article{Menzies2002,
    	abstract = "The molecular mechanisms by which mutations in the gene for Cu/Zn superoxide dismutase (SOD1) lead to the selective death of motor neurones in familial amyotrophic lateral sclerosis (FALS) remain incompletely understood. Previous evidence has indicated that mitochondrial abnormalities may develop during motor neurone injury, but several important questions remain unanswered. We have developed a cell culture model of FALS in which a motor neurone cell line (NSC34) has been stably transfected to express normal or mutant human SOD1 at levels approximating to those seen in the human disease. The aims of the study were to: (i) investigate whether morphological mitochondrial abnormalities occur at expression levels of mutant SOD1 close to physiological levels; and (ii) determine whether the presence of mutant SOD1 causes abnormalities of mitochondrial respiratory chain function and changes in cellular bioenergetic parameters in motor neuronal cells. Using this cellular model, we demonstrate that the presence of mutant SOD1 results in the development of abnormally swollen and pale staining mitochondria. These morphological changes are accompanied by biochemical abnormalities with specific decreases in the activities of complexes II and IV of the mitochondrial electron transfer chain. These same complexes are inhibited when control NSC34 cells are subjected to oxidative stress induced by serum withdrawal. The decrease in respiratory chain complex activity in the presence of mutant SOD1 was not accompanied by decreased expression of representative proteins present in these complexes. Motor neuronal cells expressing mutant SOD1 showed increased cell death when exposed to oxidative stress by serum withdrawal, whereas the presence of normal human SOD1 exerted a protective effect. Under basal, unstressed culture conditions, no change in the ATP : ADP ratio was observed in the presence of mutant SOD1. However, the mitochondrial changes associated with the presence of mutant SOD1 clearly had adverse cellular bioenergetic consequences as shown by increased cell death in the presence of pharmacological inhibition of the glycolytic pathway. We conclude that one important mechanism by which mutant SOD1 causes motor neurone injury involves inhibition of specific components of the mitochondrial electron transfer chain. Therapeutic measures aimed at protecting mitochondrial respiratory chain function may be useful in SOD1 related familial and possibly other forms of amyotrophic lateral sclerosis.",
    	author = "Menzies, Fiona M and Cookson, Mark R and Taylor, Robert W and Turnbull, Douglass M and Chrzanowska-Lightowlers, Zofia M A and Dong, Lichun and Figlewicz, Denise A and Shaw, Pamela J",
    	issn = "0006-8950",
    	journal = "Brain : a journal of neurology",
    	keywords = "Amyotrophic Lateral Sclerosis,Amyotrophic Lateral Sclerosis: metabolism,Amyotrophic Lateral Sclerosis: pathology,Animals,Cell Line,Cell Survival,Cell Survival: drug effects,Cell Survival: genetics,Culture Media, Serum-Free,Culture Media, Serum-Free: pharmacology,Electron Transport Complex I,Electron Transport Complex II,Electron Transport Complex III,Electron Transport Complex III: metabolism,Electron Transport Complex IV,Electron Transport Complex IV: metabolism,Energy Metabolism,Enzyme Activation,Enzyme Activation: drug effects,Enzyme Activation: genetics,Enzyme Inhibitors,Enzyme Inhibitors: pharmacology,Glycolysis,Glycolysis: drug effects,Humans,Iodoacetates,Iodoacetates: pharmacology,Mice,Mitochondria,Mitochondria: metabolism,Mitochondria: pathology,Mitochondria: ultrastructure,Mitochondrial Diseases,Mitochondrial Diseases: metabolism,Mitochondrial Diseases: pathology,Motor Neurons,Motor Neurons: drug effects,Motor Neurons: metabolism,Motor Neurons: pathology,Multienzyme Complexes,Multienzyme Complexes: metabolism,Mutagenesis, Site-Directed,NADH, NADPH Oxidoreductases,NADH, NADPH Oxidoreductases: metabolism,Oxidoreductases,Oxidoreductases: metabolism,Succinate Dehydrogenase,Succinate Dehydrogenase: metabolism,Superoxide Dismutase,Superoxide Dismutase: genetics,Superoxide Dismutase: metabolism,Transfection",
    	month = "",
    	number = "Pt 7",
    	pages = "1522--33",
    	pmid = 12077002,
    	title = "{Mitochondrial dysfunction in a cell culture model of familial amyotrophic lateral sclerosis.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/12077002",
    	volume = 125,
    	year = 2002
    }
    
  15. N Leclerc, F Ribera, J Zoll, J M Warter, P Poindron, E Lampert and J Borg.
    Selective changes in mitochondria respiratory properties in oxidative or glycolytic muscle fibers isolated from G93AhumanSOD1 transgenic mice.. Neuromuscular disorders : NMD 11(8):722–7, November 2001.
    Abstract Cases of familial amyotrophic lateral sclerosis (FALS) are associated with mutations in cytosolic copper, zinc superoxide dismutase (SOD1). Total SOD activity and functional mitochondrial properties were studied in muscles and nervous tissues of control and transgenic mice mimicking the disease. It was found that total SOD activity was lower in nervous tissues than in muscles in both transgenic and control mice. In addition SOD activity increased during progression of disease in muscle but not in nervous tissue of transgenic mice. Maximal oxygen consumption and apparent Km for ADP were decreased in mitochondria from transgenic soleus (an oxidative muscle). However there was no difference between control and transgenic mice in respiratory parameters of mitochondria in the EDL muscle (a glycolytic muscle). These findings indicate that oxidative stress due to SOD1 mutations could alter energy metabolism in FALS mice, thereby affecting primarily oxidative muscle of the limbs, independently of motoneuron loss.
    URL BibTeX

    @article{Leclerc2001,
    	abstract = "Cases of familial amyotrophic lateral sclerosis (FALS) are associated with mutations in cytosolic copper, zinc superoxide dismutase (SOD1). Total SOD activity and functional mitochondrial properties were studied in muscles and nervous tissues of control and transgenic mice mimicking the disease. It was found that total SOD activity was lower in nervous tissues than in muscles in both transgenic and control mice. In addition SOD activity increased during progression of disease in muscle but not in nervous tissue of transgenic mice. Maximal oxygen consumption and apparent Km for ADP were decreased in mitochondria from transgenic soleus (an oxidative muscle). However there was no difference between control and transgenic mice in respiratory parameters of mitochondria in the EDL muscle (a glycolytic muscle). These findings indicate that oxidative stress due to SOD1 mutations could alter energy metabolism in FALS mice, thereby affecting primarily oxidative muscle of the limbs, independently of motoneuron loss.",
    	author = "Leclerc, N and Ribera, F and Zoll, J and Warter, J M and Poindron, P and Lampert, E and Borg, J",
    	issn = "0960-8966",
    	journal = "Neuromuscular disorders : NMD",
    	keywords = "Adenosine Diphosphate,Adenosine Diphosphate: pharmacology,Amino Acid Substitution,Amyotrophic Lateral Sclerosis,Amyotrophic Lateral Sclerosis: genetics,Amyotrophic Lateral Sclerosis: metabolism,Animals,Brain,Brain: metabolism,Cell Respiration,Cell Respiration: genetics,Diaphragm,Diaphragm: metabolism,Disease Models, Animal,Disease Progression,Enzyme Activation,Enzyme Activation: genetics,Glycolysis,Glycolysis: genetics,Humans,Mice,Mice, Transgenic,Mitochondria, Muscle,Mitochondria, Muscle: drug effects,Mitochondria, Muscle: metabolism,Muscle, Skeletal,Muscle, Skeletal: metabolism,Organ Specificity,Oxidation-Reduction,Oxidative Phosphorylation,Oxidative Phosphorylation: drug effects,Oxygen Consumption,Spinal Cord,Spinal Cord: metabolism,Superoxide Dismutase,Superoxide Dismutase: genetics,Superoxide Dismutase: metabolism",
    	month = "nov",
    	number = 8,
    	pages = "722--7",
    	pmid = 11595514,
    	title = "{Selective changes in mitochondria respiratory properties in oxidative or glycolytic muscle fibers isolated from G93AhumanSOD1 transgenic mice.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/11595514",
    	volume = 11,
    	year = 2001
    }
    
  16. N Shibata, R Nagai, K Uchida, S Horiuchi, S Yamada, A Hirano, M Kawaguchi, T Yamamoto, S Sasaki and M Kobayashi.
    Morphological evidence for lipid peroxidation and protein glycoxidation in spinal cords from sporadic amyotrophic lateral sclerosis patients.. Brain research 917(1):97–104, October 2001.
    Abstract For determining whether both the spinal cord motor neurons and glial cells are exposed to increased oxidative stress in amyotrophic lateral sclerosis (ALS), we performed an immunohistochemical investigation of end products of lipid peroxidation and protein glycoxidation in spinal cords from seven sporadic ALS patients and seven age-matched control individuals. In the ALS spinal cords, immunoreactivities for adducts of 4-hydroxy-2-nonenal-histidine and crotonaldehyde-lysine as markers of lipid peroxidation, N(epsilon)-(carboxymethyl)lysine as a marker of lipid peroxidation or protein glycoxidation, and pentosidine as a marker of protein glycoxidation were localized in the gray matter neuropil and almost all of the motor neurons, reactive astrocytes and microglia/macrophages, whereas none of the immunoreactivities for N(epsilon)-(carboxyethyl)lysine or argpyrimidine as markers of protein glycoxidation or enzymatic glycolysis, or pyrraline or imidazolone as markers of nonoxidative protein glycation were detectable. The control spinal cords displayed no significant immunoreactivities for any of these examined products. Our results indicate that in sporadic ALS, both lipid peroxidation and protein glycoxidation are enhanced in the spinal cord motor neurons and glial cells, and suggest that the formation of certain products in these abnormal reactions is implicated in motor neuron degeneration.
    URL BibTeX

    @article{Shibata2001,
    	abstract = "For determining whether both the spinal cord motor neurons and glial cells are exposed to increased oxidative stress in amyotrophic lateral sclerosis (ALS), we performed an immunohistochemical investigation of end products of lipid peroxidation and protein glycoxidation in spinal cords from seven sporadic ALS patients and seven age-matched control individuals. In the ALS spinal cords, immunoreactivities for adducts of 4-hydroxy-2-nonenal-histidine and crotonaldehyde-lysine as markers of lipid peroxidation, N(epsilon)-(carboxymethyl)lysine as a marker of lipid peroxidation or protein glycoxidation, and pentosidine as a marker of protein glycoxidation were localized in the gray matter neuropil and almost all of the motor neurons, reactive astrocytes and microglia/macrophages, whereas none of the immunoreactivities for N(epsilon)-(carboxyethyl)lysine or argpyrimidine as markers of protein glycoxidation or enzymatic glycolysis, or pyrraline or imidazolone as markers of nonoxidative protein glycation were detectable. The control spinal cords displayed no significant immunoreactivities for any of these examined products. Our results indicate that in sporadic ALS, both lipid peroxidation and protein glycoxidation are enhanced in the spinal cord motor neurons and glial cells, and suggest that the formation of certain products in these abnormal reactions is implicated in motor neuron degeneration.",
    	author = "Shibata, N and Nagai, R and Uchida, K and Horiuchi, S and Yamada, S and Hirano, A and Kawaguchi, M and Yamamoto, T and Sasaki, S and Kobayashi, M",
    	issn = "0006-8993",
    	journal = "Brain research",
    	keywords = "Aged,Aged, 80 and over,Amyotrophic Lateral Sclerosis,Amyotrophic Lateral Sclerosis: metabolism,Amyotrophic Lateral Sclerosis: pathology,Astrocytes,Astrocytes: metabolism,Female,Glucose,Glucose: metabolism,Humans,Immunohistochemistry,Lipid Peroxides,Lipid Peroxides: metabolism,Macrophages,Macrophages: metabolism,Male,Microglia,Microglia: metabolism,Middle Aged,Motor Neurons,Motor Neurons: metabolism,Oxidation-Reduction,Proteins,Proteins: metabolism,Spinal Cord,Spinal Cord: metabolism,Spinal Cord: pathology",
    	month = "oct",
    	number = 1,
    	pages = "97--104",
    	pmid = 11602233,
    	title = "{Morphological evidence for lipid peroxidation and protein glycoxidation in spinal cords from sporadic amyotrophic lateral sclerosis patients.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/11602233",
    	volume = 917,
    	year = 2001
    }
    
  17. N Shibata, R Nagai, S Miyata, T Jono, S Horiuchi, A Hirano, S Kato, S Sasaki, K Asayama and M Kobayashi.
    Nonoxidative protein glycation is implicated in familial amyotrophic lateral sclerosis with superoxide dismutase-1 mutation.. Acta neuropathologica 100(3):275–84, 2000.
    Abstract To assess a role for oxidative stress in the pathogenesis of amyotrophic lateral sclerosis (ALS), we analyzed the immunohistochemical localization of 8-hydroxy2'-deoxyguanosine (OHdG) as a nucleic acid oxidation product, acrolein-protein adduct and 4-hydroxy-2-nonenal (HNE)-protein adduct as lipid peroxidation products, Nepsiloncarboxymethyl-lysine (CML) as a lipid peroxidation or protein glycoxidation product, pentosidine as a protein glycoxidation product, and imidazolone and pyrraline as nonoxidative protein glycation products in the spinal cord of three familial ALS patients with superoxide dismutase(SOD 1) A4V mutation, six sporadic ALS patients, and six age-matched control individuals. The spinal cord sections of the control cases did not show any distinct immunoreactivities for these examined products. In the familial ALS cases, intense immunoreactivities for pyrraline and CML were confined to the characteristic Lewy body-like hyaline inclusions, and imidazolone immunoreactivity was located in the cytoplasm of the residual motor neurons. No significant immunoreactivities for other examined products were detected in the familial ALS spinal cords. In the sporadic ALS cases, intense immunoreactivities for pentosidine, CML and HNE-protein adduct were seen in the cytoplasm of the degenerated motor neurons, and OHdG immunoreactivity was located in the cell nuclei of the residual neurons and glial cells. The present results indicate that oxidative reactions are involved in the disease processes of sporadic ALS, while there is no evidence for increased oxidative damage except for CML deposition in the familial ALS spinal cords. Furthermore, it is likely that the accumulation of pyrraline and imidazolone supports a nonoxidative mechanism in SOD1-related motor neuron degeneration.
    URL BibTeX

    @article{Shibata2000,
    	abstract = "To assess a role for oxidative stress in the pathogenesis of amyotrophic lateral sclerosis (ALS), we analyzed the immunohistochemical localization of 8-hydroxy2'-deoxyguanosine (OHdG) as a nucleic acid oxidation product, acrolein-protein adduct and 4-hydroxy-2-nonenal (HNE)-protein adduct as lipid peroxidation products, Nepsiloncarboxymethyl-lysine (CML) as a lipid peroxidation or protein glycoxidation product, pentosidine as a protein glycoxidation product, and imidazolone and pyrraline as nonoxidative protein glycation products in the spinal cord of three familial ALS patients with superoxide dismutase(SOD 1) A4V mutation, six sporadic ALS patients, and six age-matched control individuals. The spinal cord sections of the control cases did not show any distinct immunoreactivities for these examined products. In the familial ALS cases, intense immunoreactivities for pyrraline and CML were confined to the characteristic Lewy body-like hyaline inclusions, and imidazolone immunoreactivity was located in the cytoplasm of the residual motor neurons. No significant immunoreactivities for other examined products were detected in the familial ALS spinal cords. In the sporadic ALS cases, intense immunoreactivities for pentosidine, CML and HNE-protein adduct were seen in the cytoplasm of the degenerated motor neurons, and OHdG immunoreactivity was located in the cell nuclei of the residual neurons and glial cells. The present results indicate that oxidative reactions are involved in the disease processes of sporadic ALS, while there is no evidence for increased oxidative damage except for CML deposition in the familial ALS spinal cords. Furthermore, it is likely that the accumulation of pyrraline and imidazolone supports a nonoxidative mechanism in SOD1-related motor neuron degeneration.",
    	author = "Shibata, N and Nagai, R and Miyata, S and Jono, T and Horiuchi, S and Hirano, A and Kato, S and Sasaki, S and Asayama, K and Kobayashi, M",
    	issn = "0001-6322",
    	journal = "Acta neuropathologica",
    	keywords = "Acrolein,Acrolein: metabolism,Adult,Aged,Aldehydes,Aldehydes: metabolism,Amyotrophic Lateral Sclerosis,Amyotrophic Lateral Sclerosis: genetics,Amyotrophic Lateral Sclerosis: metabolism,Amyotrophic Lateral Sclerosis: pathology,Arginine,Arginine: analogs \& derivatives,Arginine: metabolism,Deoxyguanosine,Deoxyguanosine: analogs \& derivatives,Deoxyguanosine: metabolism,Glycosylation,Humans,Imidazoles,Imidazoles: metabolism,Lipid Peroxidation,Lipid Peroxidation: genetics,Lysine,Lysine: analogs \& derivatives,Lysine: metabolism,Male,Middle Aged,Motor Neurons,Motor Neurons: metabolism,Motor Neurons: pathology,Oxidative Stress,Oxidative Stress: genetics,Spinal Cord,Spinal Cord: metabolism,Spinal Cord: pathology,Spinal Cord: physiopathology,Superoxide Dismutase,Superoxide Dismutase: genetics",
    	month = "",
    	number = 3,
    	pages = "275--84",
    	pmid = 10965797,
    	title = "{Nonoxidative protein glycation is implicated in familial amyotrophic lateral sclerosis with superoxide dismutase-1 mutation.}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/10965797",
    	volume = 100,
    	year = 2000
    }
    
  18. M Konagaya, Y Konagaya, H Horikawa and M Iida.
    [Pentose phosphate pathway in neuromuscular diseases–evaluation of muscular glucose 6-phosphate dehydrogenase activity and RNA content].. Rinshō shinkeigaku = Clinical neurology 30(10):1078–83, 1990.
    Abstract There have been several reports concerning elevated glucose 6 phosphate dehydrogenase (G6PDH), the rate-limiting enzyme of pentose phosphate pathway (PPP), in experimental muscle disturbances. PPP produces ribose, a substrate of RNA, and NADPH which is a cofactor of fatty acid synthesis. PPP also has a role of by-path pathway of glycolysis. Then, we evaluated G6PDH activity and RNA content in biopsied quadriceps muscle. The subjects were muscles from 23 neurogenic amyotrophy, 54 myopathy including 19 progressive muscular dystrophy (PMD), and 10 controls whose muscle was obtained at orthopedic surgery. Neurogenic amyotrophy consisted of 12 amyotrophic lateral sclerosis (ALS), 4 spinal muscular atrophy and 7 peripheral nerve disorders. Myopathy were 3 Duchenne dystrophy, 2 congenital muscular dystrophy, 8 limb-girdle type dystrophy, 6 facio-scapular +-humeral muscular dystrophy, 6 myotonic dystrophy, 6 mitochondrial myopathy, 5 endocrinological myopathy, 3 hypokalemic myopathy, 8 polymyositis and 4 other inflammatory myopathy. The assays of G6PDH and RNA were performed after Glock's and Fleck's methods, respectively. The control values were 3.6 +/- 0.8 nmol formed NADPH/mg protein/min (M +/- SD) in G6PDH and 0.69 +/- 0.17 micrograms/mg non-collagen protein in RNA. Most cases of PMD, as well as some cases of ALS, hyperthyroidism, mitochondria hypokalemic myopathy, inflammatory myopathy showed increased values (beyond M + 2SD of control) both in G6PDH and RNA. There were significant positive correlations between G6PDH activity and RNA content in PMD and motor neuron disease. Myotonic dystrophy showed normal values in both G6PDH and RNA. Half number of cases of mitochondrial myopathy demonstrated increased G6PDH alone.(ABSTRACT TRUNCATED AT 250 WORDS)
    URL BibTeX

    @article{Konagaya1990,
    	abstract = "There have been several reports concerning elevated glucose 6 phosphate dehydrogenase (G6PDH), the rate-limiting enzyme of pentose phosphate pathway (PPP), in experimental muscle disturbances. PPP produces ribose, a substrate of RNA, and NADPH which is a cofactor of fatty acid synthesis. PPP also has a role of by-path pathway of glycolysis. Then, we evaluated G6PDH activity and RNA content in biopsied quadriceps muscle. The subjects were muscles from 23 neurogenic amyotrophy, 54 myopathy including 19 progressive muscular dystrophy (PMD), and 10 controls whose muscle was obtained at orthopedic surgery. Neurogenic amyotrophy consisted of 12 amyotrophic lateral sclerosis (ALS), 4 spinal muscular atrophy and 7 peripheral nerve disorders. Myopathy were 3 Duchenne dystrophy, 2 congenital muscular dystrophy, 8 limb-girdle type dystrophy, 6 facio-scapular +-humeral muscular dystrophy, 6 myotonic dystrophy, 6 mitochondrial myopathy, 5 endocrinological myopathy, 3 hypokalemic myopathy, 8 polymyositis and 4 other inflammatory myopathy. The assays of G6PDH and RNA were performed after Glock's and Fleck's methods, respectively. The control values were 3.6 +/- 0.8 nmol formed NADPH/mg protein/min (M +/- SD) in G6PDH and 0.69 +/- 0.17 micrograms/mg non-collagen protein in RNA. Most cases of PMD, as well as some cases of ALS, hyperthyroidism, mitochondria hypokalemic myopathy, inflammatory myopathy showed increased values (beyond M + 2SD of control) both in G6PDH and RNA. There were significant positive correlations between G6PDH activity and RNA content in PMD and motor neuron disease. Myotonic dystrophy showed normal values in both G6PDH and RNA. Half number of cases of mitochondrial myopathy demonstrated increased G6PDH alone.(ABSTRACT TRUNCATED AT 250 WORDS)",
    	author = "Konagaya, M and Konagaya, Y and Horikawa, H and Iida, M",
    	issn = "0009-918X",
    	journal = "Rinshō shinkeigaku = Clinical neurology",
    	keywords = "Adolescent,Adult,Aged,Child,Child, Preschool,Energy Metabolism,Female,Glucosephosphate Dehydrogenase,Glucosephosphate Dehydrogenase: metabolism,Humans,Infant,Male,Middle Aged,Muscles,Muscles: metabolism,Muscles: physiology,Neuromuscular Diseases,Neuromuscular Diseases: metabolism,Neuromuscular Diseases: physiopathology,RNA,RNA: metabolism,Regeneration",
    	month = "",
    	number = 10,
    	pages = "1078--83",
    	pmid = 1703936,
    	title = "{[Pentose phosphate pathway in neuromuscular diseases--evaluation of muscular glucose 6-phosphate dehydrogenase activity and RNA content].}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/1703936",
    	volume = 30,
    	year = 1990
    }
    
  19. H D Langohr.
    [Biochemical studies on muscles in neurogenic atrophies and central paralysis. Studies of the trophic functions of neurons].. Fortschritte der Medizin 98(39):1512–6, October 1980.
    Abstract Enzyme activities of the energy supplying metabolism were investigated in muscle specimens of brachial biceps, deltoid or anterior tibial muscles of patients with traumatic nerve lesions, polyneuropathies, Charcot-Marie-Tooth disease, amyotrophic lateral sclerosis, spinal muscular atrophy and hemiparesis. The key enzymes of glycogenolysis (glycogen phosphorylase), glycolysis (triosephosphate dehydrogenase, lactate dehydrogenase), alpha-glycerophosphate cycle (alpha-glycerophosphate dehydrogenase), beta-oxidation of fatty acids (beta-hydroxy-acyl-CoA-dehydrogenase), citrate acid cycle (citrate synthase, malate dehydrogenase), hexokinase reaction (hexokinase) and pentosephosphate shunt (6-phosphogluconate dehydrogenase) were measured. The present study shows that in case of disorders of the lower motor neuron–especially those with impaired axoplasmic transport–changes in the enzyme patterns of muscles occur at an early stage. The glycolytic enzyme activities are of particular significance because they are the most sensitive indicators of the onset, extent and course of neurogenic atrophy. There is a good correlation between severity of the lesion, functional state of the muscles and reduction of these enzyme activities. In case of traumatic nerve lesions re-innervation can prevent a permanent reduction of glycolytic enzymes only if it occurs during the first months after denervation. In all cases in which operative revision is considered, it is therefore not advisible to wait since the regenerative capacity of the motor neuron is not the only limiting factor but also the biochemical and morphological changes in the muscle fibre. These are permanent after long lasting denervation without re-innervation within the first months. Primary neuroaxonal degeneration of the nerve fibre which was found in the majority of our alcoholic patients obviously impairs the metabolism of the muscle to a greater extent than primary demyelination most frequently observed in diabetics with polyneuropathy. Corresponding to the chronic course of the illness over years and to the severity of the pareses, drastic reduction in the activities of glycolytic enzymes was found in patients with Charcot-Marie-Tooth disease. Simultaneously the activity of 6-phosphogluconate dehydrogenase was significantly increased as a result of the chronic neurogenic lesion of the muscle fibres. Follow-up during the treatment of diseases of the lower motor neuron can be performed because the enzyme activities can be measured even in small muscle specimens. In patients with hemiparesis slight but not significant reduction in the glycolytic enzyme activities was found by comparison with a normal control group. We assume that this reduction is due to general inactivity which is caused by the movement disorder rather than to the particular influence of the upper motor neuron.
    URL BibTeX

    @article{Langohr1980,
    	abstract = "Enzyme activities of the energy supplying metabolism were investigated in muscle specimens of brachial biceps, deltoid or anterior tibial muscles of patients with traumatic nerve lesions, polyneuropathies, Charcot-Marie-Tooth disease, amyotrophic lateral sclerosis, spinal muscular atrophy and hemiparesis. The key enzymes of glycogenolysis (glycogen phosphorylase), glycolysis (triosephosphate dehydrogenase, lactate dehydrogenase), alpha-glycerophosphate cycle (alpha-glycerophosphate dehydrogenase), beta-oxidation of fatty acids (beta-hydroxy-acyl-CoA-dehydrogenase), citrate acid cycle (citrate synthase, malate dehydrogenase), hexokinase reaction (hexokinase) and pentosephosphate shunt (6-phosphogluconate dehydrogenase) were measured. The present study shows that in case of disorders of the lower motor neuron--especially those with impaired axoplasmic transport--changes in the enzyme patterns of muscles occur at an early stage. The glycolytic enzyme activities are of particular significance because they are the most sensitive indicators of the onset, extent and course of neurogenic atrophy. There is a good correlation between severity of the lesion, functional state of the muscles and reduction of these enzyme activities. In case of traumatic nerve lesions re-innervation can prevent a permanent reduction of glycolytic enzymes only if it occurs during the first months after denervation. In all cases in which operative revision is considered, it is therefore not advisible to wait since the regenerative capacity of the motor neuron is not the only limiting factor but also the biochemical and morphological changes in the muscle fibre. These are permanent after long lasting denervation without re-innervation within the first months. Primary neuroaxonal degeneration of the nerve fibre which was found in the majority of our alcoholic patients obviously impairs the metabolism of the muscle to a greater extent than primary demyelination most frequently observed in diabetics with polyneuropathy. Corresponding to the chronic course of the illness over years and to the severity of the pareses, drastic reduction in the activities of glycolytic enzymes was found in patients with Charcot-Marie-Tooth disease. Simultaneously the activity of 6-phosphogluconate dehydrogenase was significantly increased as a result of the chronic neurogenic lesion of the muscle fibres. Follow-up during the treatment of diseases of the lower motor neuron can be performed because the enzyme activities can be measured even in small muscle specimens. In patients with hemiparesis slight but not significant reduction in the glycolytic enzyme activities was found by comparison with a normal control group. We assume that this reduction is due to general inactivity which is caused by the movement disorder rather than to the particular influence of the upper motor neuron.",
    	author = "Langohr, H D",
    	issn = "0015-8178",
    	journal = "Fortschritte der Medizin",
    	keywords = "Denervation,Humans,Motor Neurons,Motor Neurons: physiology,Muscles,Muscles: enzymology,Muscles: metabolism,Muscular Atrophy,Muscular Atrophy: enzymology,Phosphorylases,Phosphorylases: metabolism,Polyneuropathies,Polyneuropathies: enzymology",
    	month = "oct",
    	number = 39,
    	pages = "1512--6",
    	pmid = 7429410,
    	title = "{[Biochemical studies on muscles in neurogenic atrophies and central paralysis. Studies of the trophic functions of neurons].}",
    	url = "http://www.ncbi.nlm.nih.gov/pubmed/7429410",
    	volume = 98,
    	year = 1980
    }
    

Fast and Reversible Stimulation of Astrocytic Glycolysis by K+ and a Delayed and Persistent Effect of Glutamate

http://www.jneurosci.org/content/31/12/4709.full.pdf

23 March 2011

Synaptic activity is followed within seconds by a local surge in lactate concentration, a phenomenon that underlies functional magnetic resonance imaging and whose causal mechanisms are unclear, partly because of the limited spatiotemporal resolution of standard measurement techniques. Using a novel Fo¨rster resonance energy transfer-based method that allows real-time measurement of the glycolytic rate in single cells, we have studied mouse astrocytes in search forthe mechanisms responsible forthe lactate surge. Consistent with previous measurements with isotopic 2-deoxyglucose, glutamate was observedto stimulate glycolysis in cultured astrocytes, but the response appeared only after a lag period of several minutes. Naoverloads elicited by engagement of the Na-glutamate cotransporter withD-aspartate or application of the Naionophore gramicidin also failed to stimulate glycolysis in the short term. In marked contrast, Kstimulated astrocytic glycolysis byfourfold within seconds, an effectthat was observed at low millimolar concentrations and was also present in organotypic hippocampal slices. After removal of the agonists, the stimulation by K ended immediately but the stimulation by glutamate persisted unabated for20 min. Both stimulations required an active Na/K ATPase pump. By showing that small rises in extracellular K mediate short-term, reversible modulation of astrocytic glycolysis and that glutamate plays a long-term effect and leaves a metabolic trace, these results support the view that astrocytes contribute to the lactate surge that accompanies synaptic activity and underscore the role of these cells in neurometabolic and neurovascular coupling.

 


SOD1 Integrates Signals from Oxygen and Glucose to Repress Respiration
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3552299/?report=classic

 

 

Neurochem Res. 2011 May;36(5):894-903. doi: 10.1007/s11064-011-0419-0. Epub 2011 Feb 13.

Copper accelerates glycolytic flux in cultured astrocytes.

http://www.ncbi.nlm.nih.gov/pubmed/21318477

Abstract

Astrocyte-rich primary cultures were used to investigate the consequences of a copper exposure on the glucose metabolism of astrocytes. After application of CuCl(2) (30 μM) the specific cellular copper content increased from initial 1.5 ± 0.2 nmol/mg to a steady state level of 7.9 ± 0.9 nmol/mg within about 12 h. The copper accumulation was accompanied by a significant increase in the extracellular lactate concentration. The stimulating effect of copper on the lactate production remained after removal of extracellular copper. Copper treatment accelerated the rates of both glucose consumption and lactate production by about 60%. The copper induced acceleration of glycolytic flux was prevented by inhibition of protein synthesis, and additive to the stimulation of glycolysis observed for inhibitors of respiration or prolyl hydroxylases. A copper induced stimulation of glycolytic flux in astrocytes could have severe consequences for the glucose metabolism of the brain in conditions of copper overload.

PMID:
 
21318477
 
[PubMed - indexed for MEDLINE]

MeSH Terms, Substances

 

ASN Neuro. 2012 Apr 27;4(3). pii: e00086. doi: 10.1042/AN20120007.

Aspects of astrocyte energy metabolism, amino acid neurotransmitter homoeostasis and metabolic compartmentation.

http://www.asnneuro.org/an/004/e086/an004e086.htm

Abstract

Astrocytes are key players in brain function; they are intimately involved in neuronal signalling processes and their metabolism is tightly coupled to that of neurons. In the present review, we will be concerned with a discussion of aspects of astrocyte metabolism, including energy-generating pathways and amino acid homoeostasis. A discussion of the impact that uptake of neurotransmitter glutamate may have on these pathways is included along with a section on metabolic compartmentation.

PMID:
 
22435484
 
[PubMed - indexed for MEDLINE] 
PMCID:
 
PMC3338196
 
Free PMC Article