Metabolic Brain Disease

, Volume 9, Issue 1, pp 97–103 | Cite as

Cerebellar glutamate metabolizing enzymes in spinocerebellar ataxia type I

  • Stephen J. Kish
  • Li-Jan Chang
  • Lori M. Dixon
  • Yves Robitaille
  • Linda DiStefano
Original Contributions


We measured the levels of three glutamate metabolizing enzymes, namely, glutamate dehydrogenase (GDH), aspartate aminotransferase (AAT), and glutamine synthetase (GS) in cerebellar and occipital cortices of nine patients with dominantly-inherited olivopontocerebellar atrophy (OPCA; spinocerebellar ataxia type I). As compared with the controls, mean GDH activities in cerebellar cortex of the OPCA patients were normal whereas levels of AAT (−17%) and the glial enzyme GS (−27%) were significantly reduced. No statistically significant changes were observed in occipital cortex, a morphologically unaffected brain area. We suggest that the decreased GS levels could reflect impaired capacity of astrocytes to metabolize glutamate which might contribute to the degenerative processes in OPCA cerebellum.

Key words

Dominantly-inherited olivopontocerebellar atrophy spinocerebellar ataxia aspartate glutamate aspartate aminotransferase glutamate dehydrogenase glutamine synthetase 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Aoki, C., Milner, T. A., Sheu, K.-F. R., Blass, J. P., and Pickel, V. M. (1987). Regional distribution of astrocytes with intense immunoreactivity for glutamate dehydrogenase in rat brain: implications for neuron-glia interactions in glutamate transmission.J. Neurosci. 7: 2214–2231.PubMedGoogle Scholar
  2. Bhargava, H. K., and Telang, S. (1986). Postmortem changes in the enzymes of GABA and glutamate metabolism in the cerebellum and forebrain of newborn and adult rats.Neurochem. Res. 11: 1473–1478.PubMedGoogle Scholar
  3. Benveniste, H., Drejer, J., Schousboe, A., and Diemer, N. H. (1984). Elevation of the extracellular concentrations of glutamate and aspartate in rat hippocampus during transient cerebral ischemia monitored by intracerebral microdialysis.J. Neurochem. 43: 1369–1374.PubMedGoogle Scholar
  4. Carter, C. J. (1981). Loss of glutamine synthetase activity in the brain of Huntington's disease.Lancet i: 782–783.Google Scholar
  5. Carter, C. J. (1983). Glutamine synthetase and fructose-1,6-diphosphatase activity in the putamen of control and Huntington's disease brain post mortem.Life Sci. 32: 1949–1955.PubMedGoogle Scholar
  6. Dao, D. N., Ahdab-Barmada, M., and Schor, N. F. (1991). Cerebellar glutamine synthetase in children after hypoxia or ischemia.Stroke 22: 1312–1316.PubMedGoogle Scholar
  7. Derouiche, A., and Frotscher, M. (1991). Astroglial processes around identified glutamatergic synapses contain glutamine synthetase: evidence for transmitter degradation.Brain Res. 552: 346–350.PubMedGoogle Scholar
  8. Diaz, G. A., and Martinez-Rodriguez, R. (1990). Immunolocalization of cytosolic aspartate aminotransferase (cAAT) in axon terminals that form synapses in the rat cerebellar cortex. A study at the electron microscopic level.Brain Res. 516: 77–83.PubMedGoogle Scholar
  9. Erecinska, M., Pleasure, D., Nelson, D., Nissim, I., and Yudkoff, M. (1993). Cerebral aspartate utilization: near-equilibrium relationships in aspartate aminotransferase reaction.J. Neurochem. 60: 1696–1706.PubMedGoogle Scholar
  10. Farinelli, S. E., and Nicklas, W. J. (1992). Glutamate metabolism in rat cortical astrocyte cultures.J. Neurochem. 58: 1905–1915.PubMedGoogle Scholar
  11. Filla, A., De Michele, G., Morra, V. B., Palma, V., Di Lauro, A., Di Geronimo, G., and Campanella, G. (1986). Glutamate dehydrogenase in human brain: regional distribution and properties.J. Neurochem. 46: 422–424.PubMedGoogle Scholar
  12. Franic, L. I., and Martinez-Rodriguez, R. (1988). Light and electron microscope immunocytochemical localization of cytosolic aspartate aminotransferase (c-AAT-A) in the cerebellar cortex of the rat during postnatal development.Cell. Mol. Biol. 34: 7–15.PubMedGoogle Scholar
  13. Fujita, T., Doi, M., Ogata, T., Kanazawa, I., Mizusawa, H. (1993). Cerebral cortical pathology of sporadic OPCA.J. Neurolog. Sci. 116: 41–46.Google Scholar
  14. Goncalves, A., Oliveira, C., Ferro, M. A., Dinis, M., and Cunha, L. (1993). Glutamate dehydrogenase deficiency in Machado-Joseph disease.Can. J. Neurol. Sci. 20: 147–150.PubMedGoogle Scholar
  15. Grossman, A., Rosenberg, R. N., and Warmoth, L. (1987). Glutamate and malate dehydrogenase activities in Joseph disease and olivopontocerebellar atrophy.Neurology 37: 106–111.PubMedGoogle Scholar
  16. Kamisaki, Y., Inagaki, S., Tohyama, M., Horio, Y., and Wada, H. Immunocytochemical localizations of cytosolic and mitochondrial glutamic oxaloacetic transaminase isozymes in rat brain.Brain Res. 297: 363–368.Google Scholar
  17. Kihara, M., and Kubo, T. (1989). Aspartate aminotransferase for synthesis of transmitter glutamate in the medulla oblongata: effect of aminooxyacetate acid and 2-oxoglutarate.J. Neurochem. 52: 1127–1134.PubMedGoogle Scholar
  18. Kish, S. J., Robitaille, Y., El-Awar, M., Gilbert, J., Deck, J., Chang, L.-J., Schut, L. (1991). Brain amino acid reductions in one family with chromosome 6p-linked dominantly inherited olivopontocerebellar atrophy.Ann. Neurol. 30: 780–784.PubMedGoogle Scholar
  19. Kish, S. J., Bergeron, C., Rajput, A., Dozic, S., Mastrogiacomo, F., Chang, L.-J., Wilson, J. M., DiStefano, L. M., and Nobrega, J. N. (1992). Brain cytochrome oxidase in Alzheimer's disease.J. Neurochem. 59: 776–779.PubMedGoogle Scholar
  20. Kollegger, H., McBean, G. J., and Tipton, K. F. (1991). The inhibition of glutamine synthetase in rat corpus striatum in vitro by methionine sulfoximine increases the neurotoxic effects of kainate and N-methyl-D-aspartate.Neurosci. Lett. 130: 95–98.PubMedGoogle Scholar
  21. Lavoie, J., Giguère, J.-F., Pomier Layrargues, G., and Butterworth, R. F. (1987). Activities of neuronal and astrocytic marker enzymes in autopsied brain tissue from patients with hepatic encephalopathy.Metab. Brain Dis. 2: 283–290.PubMedGoogle Scholar
  22. Martinez-Hernandez, A., Bell, K. P., and Norenberg, M. D. (1977). Glutamine synthetase; glial localization in brain.Science 195: 1356–1358.PubMedGoogle Scholar
  23. Martinz-Rodriguez, R., Fernandez, B., Cevallos, C., and Gonzales, M. (1974). Histochemical localization of glutamate dehydrogenase and aspartate aminotransferase in chicken cerebellum.Brain Res. 69: 31–40.PubMedGoogle Scholar
  24. Mastrogiacomo, F. and Kish, S.J. Cerebellar α-ketoglutarate dehydrogenase activity is reduced in spinocerebellar ataxia type 1.Ann Neurol 1994 (in press).Google Scholar
  25. Norenberg, M. D., and Martinez-Hernandez, A. (1979). Fine structural localization of glutamine synthetase in astrocytes of rat brain.Brain Res. 161: 303–310.PubMedGoogle Scholar
  26. Orr, H. T., Chung, M., Banfi, S., Kwiatkowski, T. J. Jr., Servadio, A., Beaudet, A. L., McCall, A. E., Duvick, L. A., Ranum, L. P. W., and Zoghbi, H. Y. (1993). Expansion of an unstable trinucleotide CAG repeat in spinocerebellar ataxia type 1.Nature Genet 4: 221–226.PubMedGoogle Scholar
  27. Palaiologos, G., Hertz, L., and Schousboe, A. (1988). Evidence that aspartate aminotransferase activity and ketodicarboxylate carrier function are essential for biosynthesis of transmitter glutamate.J. Neurochem. 51: 317–320.PubMedGoogle Scholar
  28. Perry, T. L., Kish, S. J., Hansen, S., and Currier, R. D. (1981) Neurotransmitter amino acids in dominantly inherited cerebellar disorders.Neurology 31: 237–242.PubMedGoogle Scholar
  29. Petito, C. K., Chung, M. C., Verkhovsky, L. M., and Cooper, A. J. L. (1992). Brain glutamine synthetase increases following cerebral ischemia in the rat.Brain Res. 569: 275–280.PubMedGoogle Scholar
  30. Pishak, M. R., and Phillips, A. T. (1979). A modified radioisotopic assay for measuring glutamine synthetase activity in tissue extracts.Anal. Biochem. 94: 82–88.PubMedGoogle Scholar
  31. Quastel, J. H. (1975). Metabolic compartmentation in the brain and effects of metabolic inhibitors. In Berl, S., Clarke, D. D., and Schneider D., (eds.),Metabolic Compartmentation and Neurotransmission, Relation to Brain Structure and Function, Plenum Press, New York, pp. 337–361.Google Scholar
  32. Rao, V. L. R., and Murthy, C. R. K. (1993). Uptake and metabolism of glutamate and aspartate by astroglial and neuronal preparations of rat cerebellum.Neurochem. Res. 18: 647–654.PubMedGoogle Scholar
  33. Ritchie, T., Scully, S. A., De Vellis, J., and Noble, E. P. (1986). Stability of neuronal and glial marker enzymes in postmortem rat brain.Neurochem. Res. 11: 383–392.PubMedGoogle Scholar
  34. Schut, J. W. (1950). Hereditary ataxia: clinical study through six generations.Arch. Neurol. Psychiatry 168: 75–95.Google Scholar
  35. Tansey, F.A., Rarooq, M., Cammer, W. (1991) Glutamine synthetase in oligodendrocytes and astrocytes: New biochemical and immunocytochemical evidence.J Neurochem. 56: 266–272.PubMedGoogle Scholar
  36. Tosca, P., Canevari, L., Di Paolo, E., Ferrari, R., Verze, S., Zerbi, F., and Dagani, F. (1992). Glutamate and GABA levels in CSF from patients affected by dementia and olivo-ponto-cerebellar atrophy.Acta. Neurol. Scand. 85: 430–435.PubMedGoogle Scholar
  37. Waniewski, R. A., and McFarland, D. (1990). Intrahippocampal kainic acid reduces glutamine synthetase.Neurosci. 34: 305–310.Google Scholar
  38. Wenthold, R. J., Skaggs, K. K., and Altschuler, R. A. (1986). Immunocytochemical localization of aspartate aminotransferase and glutaminase immunoreactivities in the cerebellum.Brain Res. 363: 371–375.PubMedGoogle Scholar
  39. Wenthold, R. J., Altschuler, R. A., Skaggs, K. K., and Reeks, K. A. (1987). Immunocytochemical characterization of glutamate dehydrogenase in the cerebellum of the rat.J. Neurochem. 48: 636–643.PubMedGoogle Scholar
  40. Wurdig, S., and Kugler, P. (1991). Histochemistry of glutamate metabolizing enzymes in the rat cerebellar cortex.Neurosci. Lett. 130: 165–168.PubMedGoogle Scholar
  41. Yamamoto, H., Konno, H., Yamamoto, T., Ito, K., Mizugaki, M., and Iwasaki, Y. (1987). Glutamine synthetase of the human brain: purification and characterization.J. Neurochem. 49: 603–609.PubMedGoogle Scholar

Copyright information

© Plenum Publishing Corporation 1994

Authors and Affiliations

  • Stephen J. Kish
    • 1
  • Li-Jan Chang
    • 1
  • Lori M. Dixon
    • 1
  • Yves Robitaille
    • 2
  • Linda DiStefano
    • 1
  1. 1.Human Neurochemical Pathology LabClarke Institute of PsychiatryTorontoCanada
  2. 2.Department of PathologyUniversity of MontrealCanada

Personalised recommendations