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Neurochemical Research

, Volume 44, Issue 1, pp 154–169 | Cite as

Transgenic Mice Carrying GLUD2 as a Tool for Studying the Expressional and the Functional Adaptation of this Positive Selected Gene in Human Brain Evolution

  • Andreas PlaitakisEmail author
  • Dimitra Kotzamani
  • Zoe Petraki
  • Maria Delidaki
  • Vagelis Rinotas
  • Ioannis Zaganas
  • Eleni Douni
  • Kyriaki Sidiropoulou
  • Cleanthe Spanaki
Original Paper

Abstract

Human evolution is characterized by brain expansion and up-regulation of genes involved in energy metabolism and synaptic transmission, including the glutamate signaling pathway. Glutamate is the excitatory transmitter of neural circuits sub-serving cognitive functions, with glutamate-modulation of synaptic plasticity being central to learning and memory. GLUD2 is a novel positively-selected human gene involved in glutamatergic transmission and energy metabolism that underwent rapid evolutionary adaptation concomitantly with prefrontal cortex enlargement. Two evolutionary replacements (Gly456Ala and Arg443Ser) made hGDH2 resistant to GTP inhibition and allowed distinct regulation, enabling enhanced enzyme function under high glutamatergic system demands. GLUD2 adaptation may have contributed to unique human traits, but evidence for this is lacking. GLUD2 arose through retro-positioning of a processed GLUD1 mRNA to the X chromosome, a DNA replication mechanism that typically generates pseudogenes. However, by finding a suitable promoter, GLUD2 is thought to have gained expression in nerve and other tissues, where it adapted to their particular needs. Here we generated GLUD2 transgenic (Tg) mice by inserting in their genome a segment of the human X chromosome, containing the GLUD2 gene and its putative promoter. Double IF studies of Tg mouse brain revealed that the human gene is expressed in the host mouse brain in a pattern similar to that observed in human brain, thus providing credence to the above hypothesis. This expressional adaptation may have conferred novel role(s) on GLUD2 in human brain. Previous observations, also in GLUD2 Tg mice, generated and studied independently, showed that the non-redundant function of hGDH2 is markedly activated during early post-natal brain development, contributing to developmental changes in prefrontal cortex similar to those attributed to human divergence. Hence, GLUD2 adaptation may have influenced the evolutionary course taken by the human brain, but understanding the mechanism(s) involved remains challenging.

Keywords

GLUD2 Transgenic mice GLUD2 Adaptation  Brain hGDH2 expression Human evolution 

Abbreviations

BAC

Bacterial artificial chromosome

EDTA

Ethylenediaminetetraacetic acid

FITC

Fluorescein isothiocyanate

GFAP

Glial fibrillary acidic protein

hGDH1

Human glutamate dehydrogenase isoenzyme

hGDH2

Human glutamate dehydrogenase isoenzyme 2

IDH1

Isocitrate dehydrogenase 1

IF

Immunofluorescence

mGDH1

Mouse glutamate dehydrogenase 1

MTS

Mitochondrial targeting sequence

Tg

Transgenic

Wt

Wild-type

WB

Western blot

TCA

Tricarboxylic acid cycle

Notes

Acknowledgements

We are grateful to Stavros Drouboyiannis, Kostantina Mylonaki, Kostantina Aggelaki, Lambros Mathioudakis, Mara Bourbouli and Irene Skoula for their help in these studies.

Funding

This work was supported by the European Union (European Social Fund-ESF) and Greek national funds through the Operational Program “Education and Lifelong Learning” of the National Strategic Reference Framework (NSRF)- Research Funding Program: THALIS-UOA, Title “Mechanisms of pathogenesis of Parkinson’s disease” Grant Code (70/3/11679).

References

  1. 1.
    Bianchi S, Stimpson CD, Bauernfeind AL, Schapiro SJ, Baze WB, McArthur MJ, Bronson E, Hopkins WD, Semendeferi K, Jacobs B, Hof PR, Sherwood CC (2013) Dendritic morphology of pyramidal neurons in the chimpanzee neocortex: regional specializations and comparison to humans. Cereb Cortex 23(10):2429–2436CrossRefGoogle Scholar
  2. 2.
    Sherwood CC, Stimpson CD, Raghanti MA, Wildman DE, Uddin M, Grossman LI, Goodman M, Redmond JC, Bonar CJ, Erwin JM, Hof PR (2006) Evolution of increased glia-neuron ratios in the human frontal cortex. Proc Natl Acad Sci USA 103(37):13606–13611CrossRefGoogle Scholar
  3. 3.
    Grossman LI, Schmidt TR, Wildman DE, Goodman M (2001) Molecular evolution of aerobic energy metabolism in primates. Mol Phylogenet Evol 18(1):26–36CrossRefGoogle Scholar
  4. 4.
    Fu X, Giavalisco P, Liu X, Catchpole G, Fu N, Ning ZB, Guo S, Yan Z, Somel M, Paabo S, Zeng R, Willmitzer L, Khaitovich P (2011) Rapid metabolic evolution in human prefrontal cortex. Proc Natl Acad Sci USA 108(15):6181–6186CrossRefGoogle Scholar
  5. 5.
    Caceres M, Lachuer J, Zapala MA, Redmond JC, Kudo L, Geschwind DH, Lockhart DJ, Preuss TM, Barlow C (2003) Elevated gene expression levels distinguish human from non-human primate brains. Proc Natl Acad Sci USA 100(22):13030–13035CrossRefGoogle Scholar
  6. 6.
    Malenka RC, Nicoll RA (1993) NMDA-receptor-dependent synaptic plasticity: multiple forms and mechanisms. Trends Neurosci 16(12):521–527CrossRefGoogle Scholar
  7. 7.
    Lynch MA (2004) Long-term potentiation and memory. Physiol Rev 84(1):87–136CrossRefGoogle Scholar
  8. 8.
    Goodman M, Sterner KN (2010) Colloquium paper: phylogenomic evidence of adaptive evolution in the ancestry of humans. Proc Natl Acad Sci USA 107(Suppl 2):8918–8923CrossRefGoogle Scholar
  9. 9.
    Gomez-Robles A, Hopkins WD, Schapiro SJ, Sherwood CC (2015) Relaxed genetic control of cortical organization in human brains compared with chimpanzees. Proc Natl Acad Sci USA 112(48):14799–14804CrossRefGoogle Scholar
  10. 10.
    Muntane G, Horvath JE, Hof PR, Ely JJ, Hopkins WD, Raghanti MA, Lewandowski AH, Wray GA, Sherwood CC (2015) Analysis of synaptic gene expression in the neocortex of primates reveals evolutionary changes in glutamatergic neurotransmission. Cereb Cortex 25(6):1596–1607CrossRefGoogle Scholar
  11. 11.
    Varki A, Altheide TK (2005) Comparing the human and chimpanzee genomes: searching for needles in a haystack. Genome Res 15(12):1746–1758CrossRefGoogle Scholar
  12. 12.
    Biswas S, Akey JM (2006) Genomic insights into positive selection. Trends Genet 22(8):437–446CrossRefGoogle Scholar
  13. 13.
    O’Bleness M, Searles VB, Varki A, Gagneux P, Sikela JM (2012) Evolution of genetic and genomic features unique to the human lineage. Nat Rev Gen 13(12):853–866CrossRefGoogle Scholar
  14. 14.
    Nielsen R, Bustamante C, Clark AG, Glanowski S, Sackton TB, Hubisz MJ, Fledel-Alon A, Tanenbaum DM, Civello D, White TJ, Adams JJS, Cargill MD M (2005) A scan for positively selected genes in the genomes of humans and chimpanzees. PLoS Biol 3(6):e170CrossRefGoogle Scholar
  15. 15.
    Burki F, Kaessmann H (2004) Birth and adaptive evolution of a hominoid gene that supports high neurotransmitter flux. Nat Genet 36(10):1061–1063CrossRefGoogle Scholar
  16. 16.
    Shashidharan P, Michaelidis TM, Robakis NK, Kresovali A, Papamatheakis J, Plaitakis A (1994) Novel human glutamate dehydrogenase expressed in neural and testicular tissues and encoded by an X-linked intronless gene. J Biol Chem 269(24):16971–16976Google Scholar
  17. 17.
    Plaitakis A, Kalef-Ezra E, Kotzamani D, Zaganas I, Spanaki C (2017) The glutamate dehydrogenase pathway and its roles in cell and tissue biology in health and disease. Biology 6(1):E11.  https://doi.org/10.3390/biology6010011 CrossRefGoogle Scholar
  18. 18.
    Li WH, Yang J, Gu X (2005) Expression divergence between duplicate genes. Trends Gen 21(11):602–607.  https://doi.org/10.1016/j.tig.2005.08.006 CrossRefGoogle Scholar
  19. 19.
    Varki A (2004) How to make an ape brain. Nat Gen 36(10):1034–1036CrossRefGoogle Scholar
  20. 20.
    Spanaki C, Zaganas I, Kleopa KA, Plaitakis A (2010) Human GLUD2 glutamate dehydrogenase is expressed in neural and testicular supporting cells. J Biol Chem 285(22):16748–16756CrossRefGoogle Scholar
  21. 21.
    Spanaki C, Kotzamani D, Kleopa K, Plaitakis A (2016) Evolution of GLUD2 glutamate dehydrogenase allows expression in human cortical neurons. Mol Neurobiol 53(8):5140–5148CrossRefGoogle Scholar
  22. 22.
    Douni E, Alexiou M, Kollias G (2004) Genetic engineering in the mouse: tuning TNF/TNFR expression. Methods Mol Med 98:137–170Google Scholar
  23. 23.
    Rinotas V, Niti A, Dacquin R, Bonnet N, Stolina M, Han CY, Kostenuik P, Jurdic P, Ferrari S, Douni E (2014) Novel genetic models of osteoporosis by overexpression of human RANKL in transgenic mice. J Bone Miner Res 29(5):1158–1169CrossRefGoogle Scholar
  24. 24.
    Oberheim NA, Takano T, Han X, He W, Lin JH, Wang F, Xu Q, Wyatt JD, Pilcher W, Ojemann JG, Ransom BR, Goldman SA, Nedergaard M (2009) Uniquely hominid features of adult human astrocytes. J Neurosci 29(10):3276–3287CrossRefGoogle Scholar
  25. 25.
    Paixao S, Klein R (2010) Neuron-astrocyte communication and synaptic plasticity. Curr Opin Neurobiol 20(4):1–8CrossRefGoogle Scholar
  26. 26.
    Bao X, Pal R, Hascup KN, Wang Y, Wang WT, Xu W, Hui D, Agbas A, Wang X, Michaelis ML, Choi IY, Belousov AB, Gerhardt GA, Michaelis EK (2009) Transgenic expression of Glud1 (glutamate dehydrogenase 1) in neurons: in vivo model of enhanced glutamate release, altered synaptic plasticity, and selective neuronal vulnerability. J Neurosci 29(44):13929–13944CrossRefGoogle Scholar
  27. 27.
    Wang X, Patel ND, Hui D, Pal R, Hafez MM, Sayed-Ahmed MM, Al-Yahya AA, Michaelis EK (2014) Gene expression patterns in the hippocampus during the development and aging of Glud1 (glutamate dehydrogenase 1) transgenic and wild type mice. BMC Neurosci 15:37CrossRefGoogle Scholar
  28. 28.
    Plaitakis A, Latsoudis H, Kanavouras K, Ritz B, Bronstein JM, Skoula I, Mastorodemos V, Papapetropoulos S, Borompokas N, Zaganas I, Xiromerisiou G, Hadjigeorgiou GM, Spanaki C (2010) Gain-of-function variant in GLUD2 glutamate dehydrogenase modifies Parkinson’s disease onset. Eur J Hum Genet 18(3):336–341CrossRefGoogle Scholar
  29. 29.
    Smith TJ, Schmidt T, Fang J, Wu J, Siuzdak G, Stanley CA (2002) The structure of apo human glutamate dehydrogenase details subunit communication and allostery. J Mol Biol 318(3):765–777CrossRefGoogle Scholar
  30. 30.
    Mastorodemos V, Kanavouras K, Sundaram S, Providaki M, Petraki Z, Kokkinidis M, Zaganas I, Logothetis DE, Plaitakis A (2015) Side-chain interactions in the regulatory domain of human glutamate dehydrogenase determine basal activity and regulation. J Neurochem 133(1):73–82CrossRefGoogle Scholar
  31. 31.
    Mastorodemos V, Zaganas I, Spanaki C, Bessa M, Plaitakis A (2005) Molecular basis of human glutamate dehydrogenase regulation under changing energy demands. J Neurosci Res 79(1–2):65–73CrossRefGoogle Scholar
  32. 32.
    Aoki C, Milner TA, Berger SB, Sheu KF, Blass JP, Pickel VM (1987) Glial glutamate dehydrogenase: ultrastructural localization and regional distribution in relation to the mitochondrial enzyme, cytochrome oxidase. J Neurosci Res 18(2):305–318CrossRefGoogle Scholar
  33. 33.
    Rothe F, Wolf G, Schunzel G (1990) Immunohistochemical demonstration of glutamate dehydrogenase in the postnatally developing rat hippocampal formation and cerebellar cortex: comparison to activity staining. Neuroscience 39(2):419–429CrossRefGoogle Scholar
  34. 34.
    McKenna MC (2013) Glutamate pays its own way in astrocytes. Front Endocrinol 4:191CrossRefGoogle Scholar
  35. 35.
    Karaca M, Frigerio F, Migrenne S, Martin-Levilain J, Skytt DM, Pajecka K, Martin-del-Rio R, Gruetter R, Tamarit-Rodriguez J, Waagepetersen HS, Magnan C, Maechler P (2015) GDH-dependent glutamate oxidation in the brain dictates peripheral energy substrate distribution. Cell Rep 13(2):365–375CrossRefGoogle Scholar
  36. 36.
    Frigerio F, Karaca M, De Roo M, Mlynarik V, Skytt DM, Carobbio S, Pajecka K, Waagepetersen HS, Gruetter R, Muller D, Maechler P (2012) Deletion of glutamate dehydrogenase 1 (Glud1) in the central nervous system affects glutamate handling without altering synaptic transmission. J Neurochem 123(3):342–348CrossRefGoogle Scholar
  37. 37.
    Nissen JD, Pajecka K, Stridh MH, Skytt DM, Waagepetersen HS (2015) Dysfunctional TCA-cycle metabolism in glutamate dehydrogenase deficient astrocytes. Glia 63(12):2313–2326CrossRefGoogle Scholar
  38. 38.
    Nissen JD, Lykke K, Bryk J, Stridh MH, Zaganas I, Skytt DM, Schousboe A, Bak LK, Enard W, Paabo S, Waagepetersen HS (2017) Expression of the human isoform of glutamate dehydrogenase, hGDH2, augments TCA cycle capacity and oxidative metabolism of glutamate during glucose deprivation in astrocytes. Glia 65(3):474–488CrossRefGoogle Scholar
  39. 39.
    Farinelli SE, Nicklas WJ (1992) Glutamate metabolism in rat cortical astrocyte cultures. J Neurochem 58(5):1905–1915CrossRefGoogle Scholar
  40. 40.
    Mavrothalassitis G, Tzimagiorgis G, Mitsialis A, Zannis V, Plaitakis A, Papamatheakis J, Moschonas N (1988) Isolation and characterization of cDNA clones encoding human liver glutamate dehydrogenase: evidence for a small gene family. Proc Natl Acad Sci USA 85(10):3494–3498CrossRefGoogle Scholar
  41. 41.
    Kanavouras K, Mastorodemos V, Borompokas N, Spanaki C, Plaitakis A (2007) Properties and molecular evolution of human GLUD2 (neural and testicular tissue-specific) glutamate dehydrogenase. J Neurosci Res 85(15):3398–3406CrossRefGoogle Scholar
  42. 42.
    Borompokas N, Papachatzaki MM, Kanavouras K, Mastorodemos V, Zaganas I, Spanaki C, Plaitakis A (2010) Estrogen modification of human glutamate dehydrogenases is linked to enzyme activation state. J Biol Chem 285(41):31380–31387CrossRefGoogle Scholar
  43. 43.
    Spanaki C, Zaganas I, Kounoupa Z, Plaitakis A (2012) The complex regulation of human glud1 and glud2 glutamate dehydrogenases and its implications in nerve tissue biology. Neurochem Int 61(4):470–481CrossRefGoogle Scholar
  44. 44.
    Azarias G, Perreten H, Lengacher S, Poburko D, Demaurex N, Magistretti PJ, Chatton JY (2011) Glutamate transport decreases mitochondrial pH and modulates oxidative metabolism in astrocytes. J Neurosci 31(10):3550–3559CrossRefGoogle Scholar
  45. 45.
    Zaganas I, Plaitakis A (2002) Single amino acid substitution (G456A) in the vicinity of the GTP binding domain of human housekeeping glutamate dehydrogenase markedly attenuates GTP inhibition and abolishes the cooperative behavior of the enzyme. J Biol Chem 277(29):26422–26428CrossRefGoogle Scholar
  46. 46.
    Zaganas I, Spanaki C, Karpusas M, Plaitakis A (2002) Substitution of Ser for Arg-443 in the regulatory domain of human housekeeping (GLUD1) glutamate dehydrogenase virtually abolishes basal activity and markedly alters the activation of the enzyme by ADP and L-leucine. J Biol Chem 277(48):46552–46558CrossRefGoogle Scholar
  47. 47.
    Zaganas I, Kanavouras K, Mastorodemos V, Latsoudis H, Spanaki C, Plaitakis A (2009) The human GLUD2 glutamate dehydrogenase: localization and functional aspects. Neurochem Int 55(1–3):52–63CrossRefGoogle Scholar
  48. 48.
    Plaitakis A, Latsoudis H, Spanaki C (2011) The human GLUD2 glutamate dehydrogenase and its regulation in health and disease. Neurochem Int 59(4):495–509CrossRefGoogle Scholar
  49. 49.
    Rosso L, Marques AC, Reichert AS, Kaessmann H (2008) Mitochondrial targeting adaptation of the hominoid-specific glutamate dehydrogenase driven by positive Darwinian selection. PLoS Genet 4(8):e1000150.  https://doi.org/10.1371/journal.pgen.1000150 CrossRefGoogle Scholar
  50. 50.
    Matthews GD, Gur N, Koopman WJ, Pines O, Vardimon L (2010) Weak mitochondrial targeting sequence determines tissue-specific subcellular localization of glutamine synthetase in liver and brain cells. J Cell Sci 123(Pt 3):351–359CrossRefGoogle Scholar
  51. 51.
    Nowick K, Gernat T, Almaas E, Stubbs L (2009) Differences in human and chimpanzee gene expression patterns define an evolving network of transcription factors in brain. Proc Natl Acad Sci USA 106(52):22358–22363CrossRefGoogle Scholar
  52. 52.
    Uddin M, Wildman DE, Liu G, Xu W, Johnson RM, Hof PR, Kapatos G, Grossman LI, Goodman M (2004) Sister grouping of chimpanzees and humans as revealed by genome-wide phylogenetic analysis of brain gene expression profiles. Proc Natl Acad Sci USA 101(9):2957–2962CrossRefGoogle Scholar
  53. 53.
    Cavallaro S, Meiri N, Yi CL, Musco S, Ma W, Goldberg J, Alkon DL (1997) Late memory-related genes in the hippocampus revealed by RNA fingerprinting. Proc Natl Acad Sci USA 94(18):9669–9673CrossRefGoogle Scholar
  54. 54.
    Allen A, Kwagh J, Fang J, Stanley CA, Smith TJ (2004) Evolution of glutamate dehydrogenase regulation of insulin homeostasis is an example of molecular exaptation. Biochemistry 43(45):14431–14443CrossRefGoogle Scholar
  55. 55.
    Banerjee S, Schmidt T, Fang J, Stanley CA, Smith TJ (2003) Structural studies on ADP activation of mammalian glutamate dehydrogenase and the evolution of regulation. Biochemistry 42(12):3446–3456CrossRefGoogle Scholar
  56. 56.
    Li Q, Guo S, Jiang X, Bryk J, Naumann R, Enard W, Tomita M, Sugimoto M, Khaitovich P, Paabo S (2016) Mice carrying a human GLUD2 gene recapitulate aspects of human transcriptome and metabolome development. Proc Natl Acad Sci USA 113(19):5358–5363.  https://doi.org/10.1073/pnas.1519261113 CrossRefGoogle Scholar
  57. 57.
    Boroughs LK, DeBerardinis RJ (2015) Metabolic pathways promoting cancer cell survival and growth. Nat Cell Biol 17(4):351–359CrossRefGoogle Scholar
  58. 58.
    Carey BW, Finley LW, Cross JR, Allis CD, Thompson CB (2015) Intracellular alpha-ketoglutarate maintains the pluripotency of embryonic stem cells. Nature 518(7539):413–416CrossRefGoogle Scholar
  59. 59.
    Jin L, Li D, Alesi GN, Fan J, Kang HB, Lu Z, Boggon TJ, Jin P, Yi H, Wright ER, Duong D, Seyfried NT, Egnatchik R, DeBerardinis RJ, Magliocca KR, He C, Arellano ML, Khoury HJ, hin DM, Khuri FR, Kang S (2015) Glutamate dehydrogenase 1 signals through antioxidant glutathione peroxidase 1 to regulate redox homeostasis and tumor growth. Cancer Cell 27:257–270CrossRefGoogle Scholar
  60. 60.
    Sonnewald U, Westergaard N, Petersen SB, Unsgard G, Schousboe A (1993) Metabolism of [U-13C] glutamate in astrocytes studied by 13C NMR spectroscopy: incorporation of more label into lactate than into glutamine demonstrates the importance of the tricarboxylic acid cycle. J Neurochem 61(3):1179–1182CrossRefGoogle Scholar
  61. 61.
    Spanaki C, Kotzamani D, Plaitakis A (2017) Widening spectrum of cellular and subcellular expression of human GLUD1 and GLUD2 glutamate dehydrogenases suggests novel functions. Neurochem Res 42(1):92–107CrossRefGoogle Scholar
  62. 62.
    Bhatt DH, Zhang S, Gan WB (2009) Dendritic spine dynamics. Annu Rev Physiol 71:261–282CrossRefGoogle Scholar
  63. 63.
    Komuro H, Rakic P (1993) Modulation of neuronal migration by NMDA receptors. Science 260(5104):95–97CrossRefGoogle Scholar
  64. 64.
    Mattson MP, Dou P, Kater SB (1988) Outgrowth-regulating actions of glutamate in isolated hippocampal pyramidal neurons. J Neurosci 8(6):2087–2100CrossRefGoogle Scholar
  65. 65.
    Kwon HB, Sabatini BL (2011) Glutamate induces de novo growth of functional spines in developing cortex. Nature 474(7349):100–104CrossRefGoogle Scholar
  66. 66.
    Yang C, Sudderth J, Dang T, Bachoo RM, McDonald JG, DeBerardinis RJ (2009) Glioblastoma cells require glutamate dehydrogenase to survive impairments of glucose metabolism or Akt signaling. Cancer Res 69(20):7986–7993CrossRefGoogle Scholar
  67. 67.
    Waitkus MS, Diplas BH, Yan H (2016) Isocitrate dehydrogenase mutations in gliomas. Neuro-oncology 18(1):16–26CrossRefGoogle Scholar
  68. 68.
    Chen R, Nishimura MC, Kharbanda S, Peale F, Deng Y, Daemen A, Forrest WF, Kwong M, Hedehus M, Hatzivassiliou G, Friedman LS, Phillips HS (2014) Hominoid-specific enzyme GLUD2 promotes growth of IDH1R132H glioma. Proc Natl Acad Sci 111(39):14217–14222CrossRefGoogle Scholar
  69. 69.
    Waitkus MS, Pirozzi CJ, Moure CJ, Diplas BH, Hansen LJ, Carpenter AB, Yang R, Wang Z, Ingram BO, Karoly ED, Mohney RP, Spasojevic I, McLendon RE, Friedman HS, He Y, Bigner DD, Yan H (2018) Adaptive evolution of the GDH2 allosteric domain promotes gliomagenesis by resolving IDH1(R132H)-induced metabolic liabilities. Cancer Res 78(1):36–50CrossRefGoogle Scholar
  70. 70.
    Smits RA, van de Wijngaard WM, Stassen AP, van der Drift C (1984) Mutants of pseudomonas aeruginosa unable to inactivate allantoinase and NADP-dependent glutamate dehydrogenase. Arch Microbiol 140(1):40–43CrossRefGoogle Scholar
  71. 71.
    Britton KL, Baker PJ, Rice DW, Stillman TJ (1992) Structural relationship between the hexameric and tetrameric family of glutamate dehydrogenases. Eur J Biochem 209(3):851–859CrossRefGoogle Scholar
  72. 72.
    Huh WK, Falvo JV, Gerke LC, Carroll AS, Howson RW, Weissman JS, O’Shea EK (2003) Global analysis of protein localization in budding yeast. Nature 425(6959):686–691CrossRefGoogle Scholar
  73. 73.
    DeLuna A, Avendano A, Riego L, Gonzalez A (2001) NADP-glutamate dehydrogenase isoenzymes of Saccharomyces cerevisiae. Purification, kinetic properties, and physiological roles. J Biol Chem 276(47):43775–43783CrossRefGoogle Scholar
  74. 74.
    Campero-Basaldua C, Quezada H, Riego-Ruiz L, Marquez D, Rojas E, Gonzalez J, El-Hafidi M, Gonzalez A (2017) Diversification of the kinetic properties of yeast NADP-glutamate-dehydrogenase isozymes proceeds independently of their evolutionary origin. Microbiol Open 6 (2):e00419CrossRefGoogle Scholar
  75. 75.
    Duschak VG, Cazzulo JJ (1991) Subcellular localization of glutamate dehydrogenases and alanine aminotransferase in epimastigotes of Trypanosoma cruzi. FEMS Microbiol Lett 67(2):131–135CrossRefGoogle Scholar
  76. 76.
    Labboun S, Terce-Laforgue T, Roscher A, Bedu M, Restivo FM, Velanis CN, Skopelitis DS, Moschou PN, Roubelakis-Angelakis KA, Suzuki A, Hirel B (2009) Resolving the role of plant glutamate dehydrogenase. I. In vivo real time nuclear magnetic resonance spectroscopy experiments. Plant Cell Physiol 50(10):1761–1773CrossRefGoogle Scholar
  77. 77.
    Cammaerts D, Jacobs M (1985) A study of the role of glutamate dehydrogenase in the nitrogen metabolism of Arabidopsis thaliana. Planta 163(4):517–526CrossRefGoogle Scholar
  78. 78.
    Kotzamani D, Plaitakis A (2012) Alpha helical structures in the leader sequence of human GLUD2 glutamate dehydrogenase responsible for mitochondrial import. Neurochem Int 61(4):463–469CrossRefGoogle Scholar
  79. 79.
    Kalef-Ezra E, Kotzamani D, Zaganas I, Katrakili N, Plaitakis A, Tokatlidis K (2016) Import of a major mitochondrial enzyme depends on synergy between two distinct helices of its presequence. Biochem J 473(18):2813–2829CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Andreas Plaitakis
    • 1
    • 2
    Email author
  • Dimitra Kotzamani
    • 1
  • Zoe Petraki
    • 1
  • Maria Delidaki
    • 1
  • Vagelis Rinotas
    • 3
  • Ioannis Zaganas
    • 1
  • Eleni Douni
    • 3
    • 4
  • Kyriaki Sidiropoulou
    • 5
  • Cleanthe Spanaki
    • 1
  1. 1.Department of Neurology, School of MedicineUniversity of CreteHeraklionGreece
  2. 2.Neurology DepartmentIcahn School of Medicine at Mount SinaiNew YorkUSA
  3. 3.Division of ImmunologyBiomedical Sciences Research Center “Alexander Fleming”VariGreece
  4. 4.Laboratory of Genetics, Department of BiotechnologyAgricultural University of AthensAthensGreece
  5. 5.Department of BiologyUniversity of CreteHeraklionGreece

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