Hostname: page-component-586b7cd67f-gb8f7 Total loading time: 0 Render date: 2024-11-23T20:42:48.924Z Has data issue: false hasContentIssue false
  • English
  • Français

Glutamate Dehydrogenase Deficiency in Cerebellar Degenerations: Clinical, Biochemical and Molecular Genetic Aspects

Published online by Cambridge University Press:  18 September 2015

Plaitakis Andreas ,
Flessas Panayiotis ,
B. Natsiou Anastasia  and
P. Shashidharan
Plaitakis Andreas*
Affiliation:
Department of Neurology, Mount Sinai School of Medicine, New York (A.P., P.S.); University of Crete, School of Health Sciences, Iraklion, Crete, Greece (P.F., A.B.N.)
Flessas Panayiotis*
Affiliation:
Department of Neurology, Mount Sinai School of Medicine, New York (A.P., P.S.); University of Crete, School of Health Sciences, Iraklion, Crete, Greece (P.F., A.B.N.)
B. Natsiou Anastasia*
Affiliation:
Department of Neurology, Mount Sinai School of Medicine, New York (A.P., P.S.); University of Crete, School of Health Sciences, Iraklion, Crete, Greece (P.F., A.B.N.)
P. Shashidharan*
Affiliation:
Department of Neurology, Mount Sinai School of Medicine, New York (A.P., P.S.); University of Crete, School of Health Sciences, Iraklion, Crete, Greece (P.F., A.B.N.)
*
Department of Neurology, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, N.Y., USA 10029
Rights & Permissions [Opens in a new window]

Abstract:

Core share and HTML view are not available for this content. However, as you have access to this content, a full PDF is available via the ‘Save PDF’ action button.

Glutamate dehydrogenase (GDH), an enzyme central to glutamate metabolism, is significantly reduced in patients with heterogenous neurological disorders characterized by multiple system atrophy (MSA) and predominant involvement of the cerebellum and its connections. In human brain, GDH exists in multiple isoforms differing in their isoelectric point and molecular mass. These are differentially reduced in quantity and altered in catalytic activity in patients with clinically distinct forms of MSA, thus suggesting that these GDH isoproteins are under different genetic control. Dysregulation of glutamate metabolism occurs in patients with GDH deficiency and is thought to mediate the disease’s neurodegeneration via neuroexcitotoxic mechanisms. This possibility is supported by additional data showing that glutamate binding sites are significantly decreased in cerebellar tissue obtained at autopsy from MSA patients. At the molecular biological level, several cDNAs specific for human GDH have been isolated recently and cloned. Northern blot analysis of various human tissues, including brain, has revealed the presence of multiple GDH-specific mRNAs. In addition, multiple GDH-specific genes are present in humans and these data are consistent with the possibility that the various GDH isoproteins are encoded by different genes. These advances have laid the groundwork for characterizing the human GDH genes and their products in health and disease.

Type
Abstract
Information
Canadian Journal of Neurological Sciences , Volume 20 , Issue S3 , May 1993 , pp. S109 - S116
Copyright
Copyright © Canadian Neurological Sciences Federation 1993

References

REFERENCES

1.Plaitakis, A, Nicklas, WJ, Desnick, RJ.Glutamate dehydrogenase deficiency in three patients with spinocerebellar ataxia: a new enzymatic defect? Trans Am Neurol Assoc 1979; 104: 54–57.Google ScholarPubMed
2.Plaitakis, A, Nicklas, WJ, Desnick, RJ.Glutamate dehydrogenase deficiency in three patients with spinocerebellar syndrome. Ann Neurol 1980; 7: 297–303.CrossRefGoogle ScholarPubMed
3.Desclin, JC, Escubi, J.Effects of 3-acetylpyridine on the central nervous system of the rat as demonstrated by silver methods. Brain Res 1974; 77: 349–364.CrossRefGoogle ScholarPubMed
4.Herken, H.Functional disorders of the brain induced by synthesis of nucleotides containing 3-acetylpyridine. Z Klin Chem 1968; 6: 635–367.Google ScholarPubMed
5.Plaitakis, A, Berl, S.Oral glutamate loading in disorders with spinocerebellar and extrapyramidal involvement: effect on plasma glutamate, aspartate and taurine. J Neural Transm 1983; (Suppl 19): 65–74.Google ScholarPubMed
6.Plaitakis, A, Berl, S, Yahr, M.D.Neurological disorders associated with deficiency of glutamate dehydrogenase. Ann Neurol 1984; 15: 144–153.CrossRefGoogle ScholarPubMed
7.Plaitakis, A.Abnormal metabolism of neuroexcitatory amino acids in olivopontocerebellar atrophy. In: Duvoisin, RC, Plaitakis, A, eds. The Olivopontocerebellar Atrophies. Adv Neurol. New York: Raven Press 1984; 41: 225–243.Google ScholarPubMed
8.Plaitakis, A.Classification and epidemiology of cerebellar degeneration. In: Plaitakis, A, ed. Cerebellar Degenerations: Clinical Neurobiology. Boston: Kluwer Academic Publishers 1992; 185–204.CrossRefGoogle Scholar
9.Plaitakis, A, Yahr, MD.Abnormalities in GDH and glutamate metabolism in atypical Parkinson’s disease and progressive supranuclear palsy. Neurology 1986; 35 (Suppl 1): 110.Google Scholar
10.Haines, JL, Schut, LJ, Weikamp, LR, et al.Spinocerebellar ataxia in a large kindred: age at onset, reproduction, and genetic linkage studies. Neurology 1984; 34: 1542–1548.Google Scholar
11.Smith, EL, Austen, BM, Blumenthal, KM, Nyc, JF.Glutamate dehydrogenases. In: Boyer, , ed. The Enzymes. New York: Academic Press 1975; 293–367.Google Scholar
12.Colon, A, Piaitakis, A, Perakis, A, et al.Purification and characterzation of a soluble and a particulate glutamate dehydrogenase from rat brain. J Neurochem 1986; 46: 1811–1819.CrossRefGoogle Scholar
13.Plaitakis, A.Biochemistry of recessive olivopontocerebellar atrophy. Ital J Neurol Sci 1984; (Suppl 4): 65–73.Google Scholar
14.Konagaya, Y, Konagaya, M, Takayanagi, T.Glutamate dehydrogenase and its isozyme activity in olivopontocerebellar atrophy. J Neurol Sci 1986; 74: 231–236.Google ScholarPubMed
15.Duvoisin, RC, Nicklas, WJ, Ritchie, V, et al.Low leukocyte glutamate dehydrogenase activity does not correlate with a particular type of multiple system atrophy. J Neurol Neurosurg Psychiatry 1988; 51: 1508–1511.CrossRefGoogle Scholar
16.Aubby, D, Saggu, HK, Jenner, P, et al.Leukocyte glutamate dehydrogenase activity in patients with degenerative neurological disorders. J Neurol Neurosurg Psychiatry 1988; 51: 893–902.CrossRefGoogle ScholarPubMed
17.Hussain, MM, Zannis, V, Plaitakis, A.Characterization of glutamate dehydrogenase isoproteins purified from the cerebellum of normal subjects and patients with degenerative neurological disorders, and from human neoplastic cell lines. J Biol Chem 1989; 264: 20730–20735.CrossRefGoogle ScholarPubMed
18.Yamaguchi, T, Hayashi, K, Murakami, H, et al.Glutamate dehydro-genase deficiency in spinocerebellar degenerations. Neurochem Res 1982; 7: 627–636.CrossRefGoogle Scholar
19.Duvoisin, RC, Chokroverty, S, Lepore, F, Nicklas, WJ.Glutamate dehydrogenase deficiency in patients with olivopontocerebellar atrophy. Neurology 1983; 33: 1322–1326.CrossRefGoogle ScholarPubMed
20.Chokroverty, S, Duvoisin, RC, Sacheo, R, et al.Neurophysiologic study of olivopontocerebellar atrophy with or without glutamate dehydrogenase deficiency. Neurology 1985; 35: 652–659.CrossRefGoogle ScholarPubMed
21.Sorbi, S, Tonini, S, Giannini, E, Piacetini, S, et al.Abnormal platelet glutamate dehydrogenase activity and activation in dominant and non-dominant olivopontocerebellar atrophy. Ann Neurol 1986; 19: 239–245.CrossRefGoogle Scholar
22.Sorbi, S, Piacetini, S, et al.Abnormalities of mitochondrialenzymes in hereditary ataxias. Acta Neurol Scand 1989; 80: 103–110.CrossRefGoogle ScholarPubMed
23.Finocchiaro, G, Taroni, F, DI Donato, S.Glutamate dehydrogenase in olivopontocerebellar atrophies: leukocytes, fibroblasts, and muscle mitochondria. Neurology 1986; 36: 550–553.Google ScholarPubMed
24.Kostic, VS, Mojsilivic, LJ, Stojanovic, M.Degenerative neurological disorders associated with deficiency of glutamate dehydrogenase. J Neurol 1989; 236: 101–114.Google ScholarPubMed
25.Orsi, L, Bertolotto, A, Bringolio, F, et al.Glutamate dehydrogenase (GDH) deficiency in different types of progressive hereditary cerebellar ataxia. Acta Neurol Scand 1988; 78: 394–400.CrossRefGoogle ScholarPubMed
26.Kajiyama, K, Ueno, S, Tatsumi, T, et al.Decreased glutamate dehydrogenase protein in spinocerebellar degeneration. J Neurol Neurosurg Psychiatry 1988; 51: 1078–1080.CrossRefGoogle ScholarPubMed
27.Tatsumi, C, Yorifuji, S, Takahashi, M, Tarui, S.Decreased viability of skin fibroblasts from patients with glutamate dehydrogenase deficiency. Neurology 1989; 39: 541–452.CrossRefGoogle ScholarPubMed
28.Iwattsuji, K, Nakamura, S, Kameyama, M.Lymphocyte glutamate dehydrogenase activity in normal aging and neurological diseases. Gerontology 1989; 35: 218–224.CrossRefGoogle Scholar
29.Kaakola, S, Marnela, K-M, Oja, SS, et al.Leukocyte glutamate dehydrogenase and CSF amino acids in late onset ataxias. Acta Neurol Seand 1990; 82: 225–229.CrossRefGoogle Scholar
29a.Abe, T, Ishiguro, S-I, Saito, H, et al.Partially deficient glutamate dehydrogenase activity and attenuated oscillatory potentials in patients with spinocerebellar degeneration. Invest Ophthalmol Vis Sci 1992; 33: 447–452.Google ScholarPubMed
30.piaitakis, A, Berl, S, Yahr, MD.Abnormal glutamate metabolism in adult-onset degenerative neurological disorder. Science 1982; 216: 193–196.CrossRefGoogle Scholar
31.Sawada, H, Seriu, N, Udaka, F, et al.Cerebellar ataxia with glutamic aciduria. Acta Neurol Scand 1991; 84: 70–72.CrossRefGoogle ScholarPubMed
32.Aoki, C, Milner, TA, Rex Sheu, K-FR, et al.Regional distribution of astrocytes with intense immunoreactivity for glutamate dehydrogenase in rat brain: implications for neuron-glia interactions in glutamate transmission. J Neurosci 1987; 7: 2214–2231.CrossRefGoogle ScholarPubMed
33.Fonnum, F.Glutamate: a neurotransmitter in mammalian brain. J Neurochem 1984; 42: 1–11.CrossRefGoogle ScholarPubMed
34.Balcar, VJ, Borg, J, Mandel, P.High affinity uptake of L-glutamate and L-aspartate by glial cells. J Neurochem 1977; 27–28.CrossRefGoogle Scholar
35.Hertz, L, Schousboe, A.Metabolism of glutamate and glutamine in neurons and astrocytes in primary cultures. In: Kvamme, E, ed. Glutamine and Glutamate in Mammals. Boca Raton, FL, CRC Press 1988; II: 39–55.Google Scholar
36.Shank, RP, Aprison, MH.Glutamate as neurotransmitter. In: Kvamme, E, ed. Glutamine and Glutamate in Mammals. Boca Raton, FL, CRC Press 1988; II: 3–19.Google Scholar
37.Huang, YP, Plaitakis, A.Morphological changes in olivopontocere-bellar atrophy in computed tomography and comments on its pathogenesis. In: Duvoisin, RC, Plaitakis, A, eds. The Olivopontocerebellar Atrophies. Adv Neurol. New York: Raven Press 1984; 41: 39–81.Google ScholarPubMed
38.Plaitakis, A.Olivopontocerebellar atrophy with glutamate dehydrogenase deficiency. In: JMBV, de Jong, ed. Handbook of Clinical Neurology, Hereditary Neuropathies and Spinocerebellar Atrophies. Amsterdam: Elsevier Science Publishers 1990; 16(60):551–568.Google Scholar
39.Chee, PY, Dahl, LJ, Fahien, A.The purification and properties of rat brain glutamate dehydrogenase. J Neurochem 1979; 33: 53–60).CrossRefGoogle ScholarPubMed
40.Pearce, IA, Cambray-Deakin, MA, Burgyne, RD.Glutamate acting on NMDA receptors stimulates neurite outgrowth from cerebellar granule cells. FEBS Lett 1987; 233: 143–147.CrossRefGoogle Scholar
41.Balazs, R, Hack, N, Jorgensen, OS.Stimulation of the N-methyl-D-aspartate receptor has a trophic effect on differentiating cerebellar granule cells. Neurosci Lett 1988; 87: 80–86.Google Scholar
42.Tsiotos, P, Plaitakis, A, Mitsakos, A, et al.L-glutamate binding sites of normal and atrophic human cerebellum. Brain Res 1989; 481: 87–96.CrossRefGoogle ScholarPubMed
43.Hatziefthimiou, A, Mitsakos, A, Mitsaki, E, et al.Quantitative autoradiographic study of L-glutamate binding studies in normal and atrophic human cerebellum. J Neurosci Res 1991; 28: 367–375.CrossRefGoogle ScholarPubMed
44.Albin, RL, Gilman, S.Autoradiographic localization of inhibitory and excitatory amino acid transmitter receptors in human normal and olivopontocerebellar atrophy cerebellum. Brain Res 1990; 522: 37–45.CrossRefGoogle Scholar
45.Macowiec, RL, Albin, RL, Cha, JJ, et al.Two types of quisqualate receptor are reduced in human OPCA cerebellar cortex. Brain Res 1990; 552: 37–45.Google Scholar
46.Jung, KY, Warter, S, Rumpler, Y.Assignment of the GDH loci to human chromosomes 10q23 and Xq24 by in situ hybridization. Ann Genet 1989; 32: 109–110.Google ScholarPubMed
47.Anagnou, NP, Senanez, H, Modi, SJ, et al.Chromosomal mapping of the human glutamate dehydrogenase (GLUD) genes to chromosomes 10 q21.1-21.2 and X q26-28. Am Soc Hum Genet 1989; 45: A170.Google Scholar
48.Rich, SS, Wilkie, PJ, Schut, LJ, et al.Spinocerebellar ataxia: localization of an autosomal dominant locus between two markers on human chromosome 6. Am J Hum Genet 1987; 41: 524–531.Google ScholarPubMed
49.Banner, C, Silverman, S, Thomas, JW, et al.Isolation of a human cDNA clone for glutamate dehydrogenase. J Neurochem 1987; 49: 246–252.CrossRefGoogle Scholar
50.Maurothalassitis, G, Tzimagiorgis, G, Mitsialis, A, et al.Isolation and characterization of cDNA clones encoding human liver glutarnate dehydrogenase: evidence for a small gene family. Proc Natl Acad Sci USA 1988; 85: 3494–3498.CrossRefGoogle Scholar
51.Hanauer, A, Mattei, MG, Mandel, JL.Presence of a tag I polymorphism in the human glutamate dehydrogenase (GLUD) gene on chomosome 10. Nucleic Acid Res 1987; 15: 6308.CrossRefGoogle Scholar
52.Amuro, N, Goto, Y, Okazaki, T.Isolation and characterization of two distinct genes for human glutamate dehydrogenase. Biochem Biophys Acta 1990; 1049: 216–218.Google ScholarPubMed
53.Saiki, RK, Gelfard, DH, Stoffel, SV, et al.Primer-directed enzymatic amplification of DNA with a thermostable DNA polymerase. Science 1988; 239: 487–491.CrossRefGoogle ScholarPubMed
54.Randall, K, Saiki, RK.Amplification of genomic DNA. In: Innis, MA, Gelfand, DH, Sninsky, JJ, White, TJ, eds. PCR Protocols. A Guide to Methods and Applications. San Diego: Academic Press 1990; 13–20.Google Scholar
55.Gibbs, RA.DNA Amplification by the polymerase chain reaction. Anal Chem 1990; 62: 1202–1214.CrossRefGoogle ScholarPubMed
56.Michaelidis, TM, Tzimagiorgis, G, Moschonas, NK, Papamatheakis, J.The human glutamate dehydrogenase gene family: Gene organization and structural characterization. Genomics, 1993 (in press).Google Scholar