Journal of Molecular Neuroscience

, Volume 64, Issue 3, pp 385–396 | Cite as

In Silico Preliminary Association of Ammonia Metabolism Genes GLS, CPS1, and GLUL with Risk of Alzheimer’s Disease, Major Depressive Disorder, and Type 2 Diabetes

  • Jeddidiah W. D. Griffin
  • Ying Liu
  • Patrick C. Bradshaw
  • Kesheng Wang
Article
First Online:
Received:
Accepted:
  • 69 Downloads

Abstract

Ammonia is a toxic by-product of protein catabolism and is involved in changes in glutamate metabolism. Therefore, ammonia metabolism genes may link a range of diseases involving glutamate signaling such as Alzheimer’s disease (AD), major depressive disorder (MDD), and type 2 diabetes (T2D). We analyzed data from a National Institute on Aging study with a family-based design to determine if 45 single nucleotide polymorphisms (SNPs) in glutaminase (GLS), carbamoyl phosphate synthetase 1 (CPS1), or glutamate-ammonia ligase (GLUL) genes were associated with AD, MDD, or T2D using PLINK software. HAPLOVIEW software was used to calculate linkage disequilibrium measures for the SNPs. Next, we analyzed the associated variations for potential effects on transcriptional control sites to identify possible functional effects of the SNPs. Of the SNPs that passed the quality control tests, four SNPs in the GLS gene were significantly associated with AD, two SNPs in the GLS gene were associated with T2D, and one SNP in the GLUL gene and three SNPs in the CPS1 gene were associated with MDD before Bonferroni correction. The in silico bioinformatic analysis suggested probable functional roles for six associated SNPs. Glutamate signaling pathways have been implicated in all these diseases, and other studies have detected similar brain pathologies such as cortical thinning in AD, MDD, and T2D. Taken together, these data potentially link GLS with AD, GLS with T2D, and CPS1 and GLUL with MDD and stimulate the generation of testable hypotheses that may help explain the molecular basis of pathologies shared by these disorders.

Keywords

Ammonia Glutamate Alzheimer’s disease Major depressive disorder Type 2 diabetes 
This is a preview of subscription content, log in to check access

Notes

Acknowledgments

We acknowledge the NIH GWAS Data Repository, the Contributing Investigator(s) who contributed the phenotype data and DNA samples from his/her original study, and the primary funding organization that supported the contributing study “National Institute on Aging—Late Onset Alzheimer’s Disease Family Study: Genome-Wide Association Study for Susceptibility Loci.” The datasets used for analyses described in this manuscript were obtained from dbGaP at http://www.ncbi.nlm.nih.gov/gap through dbGaP accession number phs000219.v1.p1. Funding support for the “Genetic Consortium for Late Onset Alzheimer’s Disease” was provided through the Division of Neuroscience, NIA. The Genetic Consortium for Late Onset Alzheimer’s Disease includes a genome-wide association study funded as part of the Division of Neuroscience, NIA. Assistance with phenotype harmonization and genotype cleaning, as well as with general study coordination, was provided by the Genetic Consortium for Late Onset Alzheimer’s Disease. In addition, JG would like to thank Wayne C. Birchfield for directing his attention to the role of ammonia metabolism in cognitive functioning.

Author Contributions

JG and KW performed the research, and JG wrote the first draft of the manuscript. PB, KW, and YL contributed to the content of the manuscript. All authors have approved the final version of this article.

Compliance with Ethical Standards

Conflicts of Interest

The authors declare that they have no conflict of interest.

References

  1. Akiyama H, McGeer PL, Itagaki S et al (1989) Loss of glutaminase-positive cortical neurons in Alzheimer’s disease. Neurochem Res 14(4):353–358.  https://doi.org/10.1007/BF01000038 CrossRefPubMedGoogle Scholar
  2. Ali S, Stone MA, Peters JL, Davies MJ, Khunti K (2006) The prevalence of co-morbid depression in adults with type 2 diabetes: a systematic review and meta-analysis. Diabet Med 23(11):1165–1173.  https://doi.org/10.1111/j.1464-5491.2006.01943.x CrossRefPubMedGoogle Scholar
  3. Amidfar M, Khiabany M, Kohi A, Salardini E, Arbabi M, Roohi Azizi M, Zarrindast MR, Mohammadinejad P, Zeinoddini A, Akhondzadeh S (2017) Effect of memantine combination therapy on symptoms in patients with moderate-to-severe depressive disorder: randomized, double-blind, placebo-controlled study. J Clin Pharm Ther 42(1):44–50.  https://doi.org/10.1111/jcpt.12469 CrossRefPubMedGoogle Scholar
  4. Anderson RJ, Freedland KE, Clouse RE, Lustman PJ (2001) The prevalence of comorbid depression in adults with diabetes: a meta-analysis. Diabetes Care 24(6):1069–1078.  https://doi.org/10.2337/diacare.24.6.1069 CrossRefPubMedGoogle Scholar
  5. Angelin A, Gil-de-Gómez L, Dahiya S, Jiao J, Guo L, Levine MH, Wang Z, Quinn WJ III, Kopinski PK, Wang L, Akimova T, Liu Y, Bhatti TR, Han R, Laskin BL, Baur JA, Blair IA, Wallace DC, Hancock WW, Beier UH (2017) Foxp3 reprograms T cell metabolism to function in low-glucose, high-lactate environments. Cell Metab 25(6):1282–1293.e7.  https://doi.org/10.1016/j.cmet.2016.12.018 CrossRefPubMedGoogle Scholar
  6. Ardawi MSM (1987) The maximal activity of phosphate-dependent glutaminase and glutamine metabolism in the colon and the small intestine of streptozotocin-diabetic rats. Diabetologia 30(2):109–114.  https://doi.org/10.1007/bf00274581 PubMedGoogle Scholar
  7. Auron A, Brophy PD (2012) Hyperammonemia in review: pathophysiology, diagnosis, and treatment. Pediatr Nephrol 27(2):207–222.  https://doi.org/10.1007/s00467-011-1838-5 CrossRefPubMedGoogle Scholar
  8. Barrett JC, Fry B, Maller J, Daly MJ (2005) Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21(2):263–265.  https://doi.org/10.1093/bioinformatics/bth457 CrossRefPubMedGoogle Scholar
  9. Bernard R, Kerman IA, Thompson RC, Jones EG, Bunney WE, Barchas JD, Schatzberg AF, Myers RM, Akil H, Watson SJ (2011) Altered expression of glutamate signaling, growth factor, and glia genes in the locus coeruleus of patients with major depression. Mol Psychiatry 16(6):634–646.  https://doi.org/10.1038/mp.2010.44 CrossRefPubMedGoogle Scholar
  10. Bovolenta LA, Acencio ML, Lemke N (2012) HTRIdb: an open-access database for experimentally verified human transcriptional regulation interactions. BMC Genomics 13(1):405.  https://doi.org/10.1186/1471-2164-13-405 CrossRefPubMedCentralPubMedGoogle Scholar
  11. Burbaeva GS, Boksha IS, Tereshkina EB, Savushkina OK, Prokhorova TA, Vorobyeva EA (2014) Glutamate and GABA-metabolizing enzymes in post-mortem cerebellum in Alzheimer’s disease: phosphate-activated glutaminase and glutamic acid decarboxylase. Cerebellum 13(5):607–615.  https://doi.org/10.1007/s12311-014-0573-4 CrossRefPubMedGoogle Scholar
  12. Cantley J, Ashcroft FM (2015) Q&A: insulin secretion and type 2 diabetes: why do β-cells fail? BMC Biol 13(1):33.  https://doi.org/10.1186/s12915-015-0140-6 CrossRefPubMedCentralPubMedGoogle Scholar
  13. Chandley MJ, Szebeni K, Szebeni A, Crawford J, Stockmeier A, Turecki G, Miguel-Hidalgo J, Ordway G (2013) Gene expression deficits in pontine locus coeruleus astrocytes in men with major depressive disorder. J Psychiatry Neurosci 38(4):276–284.  https://doi.org/10.1503/jpn.120110 CrossRefPubMedCentralPubMedGoogle Scholar
  14. Choudary PV, Molnar M, Evans SJ, Tomita H, Li JZ, Vawter MP, Myers RM, Bunney WE, Akil H, Watson SJ, Jones EG (2005) Altered cortical glutamatergic and GABAergic signal transmission with glial involvement in depression. Proc Natl Acad Sci U S A 102(43):15653–15658.  https://doi.org/10.1073/pnas.0507901102 CrossRefPubMedCentralPubMedGoogle Scholar
  15. Chung SJ, Kim M-J, Kim J, Ryu HS, Kim YJ, Kim SY, Lee JH (2015) Association of type 2 diabetes GWAS loci and the risk of Parkinson’s and Alzheimer’s diseases. Parkinsonism Relat Disord 21(12):1435–1440.  https://doi.org/10.1016/j.parkreldis.2015.10.010 CrossRefPubMedGoogle Scholar
  16. Cooper AJL, Jeitner TM (2016) Central role of glutamate metabolism in the maintenance of nitrogen homeostasis in normal and hyperammonemic brain. Biomol Ther 6(2).  https://doi.org/10.3390/biom6020016
  17. Crosby ME, Almasan A (2004) Opposing roles of E2Fs in cell proliferation and death. Cancer Biol Ther 3(12):1208–1211.  https://doi.org/10.4161/cbt.3.12.1494 CrossRefPubMedCentralPubMedGoogle Scholar
  18. Desmet F-O, Hamroun D, Lalande M, Collod-Béroud G, Claustres M, Béroud C (2009) Human Splicing Finder: an online bioinformatics tool to predict splicing signals. Nucleic Acids Res 37(9):e67–e67.  https://doi.org/10.1093/nar/gkp215 CrossRefPubMedCentralPubMedGoogle Scholar
  19. Dimski DS (1994) Ammonia metabolism and the urea cycle: function and clinical implications. J Vet Intern Med 8(2):73–78.  https://doi.org/10.1111/j.1939-1676.1994.tb03201.x CrossRefPubMedGoogle Scholar
  20. Dittmer J (2003) The biology of the Ets1 proto-oncogene. Mol Cancer 2(1):29.  https://doi.org/10.1186/1476-4598-2-29 CrossRefPubMedCentralPubMedGoogle Scholar
  21. Drucker DJ, Sherman SI, Gorelick FS, Bergenstal RM, Sherwin RS, Buse JB (2010) Incretin-based therapies for the treatment of type 2 diabetes: evaluation of the risks and benefits. Diabetes Care 33(2):428–433.  https://doi.org/10.2337/dc09-1499 CrossRefPubMedCentralPubMedGoogle Scholar
  22. Du A-T, Schuff N, Kramer JH et al (2007) Different regional patterns of cortical thinning in Alzheimer’s disease and frontotemporal dementia. Brain 130(4):1159–1166.  https://doi.org/10.1093/brain/awm016 CrossRefPubMedCentralPubMedGoogle Scholar
  23. Esposito Z, Belli L, Toniolo S, Sancesario G, Bianconi C, Martorana A (2013) Amyloid B, glutamate, excitotoxicity in Alzheimer’s disease: are we on the right track? CNS Neurosci Ther 19(8):549–555.  https://doi.org/10.1111/cns.12095 CrossRefPubMedGoogle Scholar
  24. Finckh U, Kohlschütter A, Schäfer H, Sperhake K, Colombo JP, Gal A (1998) Prenatal diagnosis of carbamoyl phosphate synthetase I deficiency by identification of a missense mutation in CPS1. Hum Mutat 12(3):206–211.  https://doi.org/10.1002/(SICI)1098-1004(1998)12:3<206::AID-HUMU8>3.0.CO;2-E CrossRefPubMedGoogle Scholar
  25. Fisman M, Gordon B, Feleki V, Helmes E, Appell J, Rabheru K (1985) Hyperammonemia in Alzheimer’s disease. Am J Psychiatry 142(1):71–73.  https://doi.org/10.1176/ajp.142.1.71 CrossRefPubMedGoogle Scholar
  26. Gao L, Cui Z, Shen L, Ji H-F (2016) Shared genetic etiology between type 2 diabetes and Alzheimer’s disease identified by bioinformatics analysis. J Alzheimers Dis 50(1):13–17.  https://doi.org/10.3233/JAD-150580 CrossRefPubMedGoogle Scholar
  27. Gatz M, Pedersen NL, Berg S, et al (1997) Heritability for Alzheimer’s disease: the study of dementia in Swedish twins. J Gerontol 52:117–125Google Scholar
  28. Geerlings MI, den Heijer T, Koudstaal PJ, Hofman A, Breteler MMB (2008) History of depression, depressive symptoms, and medial temporal lobe atrophy and the risk of Alzheimer disease. Neurology 70(15):1258–1264.  https://doi.org/10.1212/01.wnl.0000308937.30473.d1 CrossRefPubMedGoogle Scholar
  29. Gheni G, Ogura M, Iwasaki M, Yokoi N, Minami K, Nakayama Y, Harada K, Hastoy B, Wu X, Takahashi H, Kimura K, Matsubara T, Hoshikawa R, Hatano N, Sugawara K, Shibasaki T, Inagaki N, Bamba T, Mizoguchi A, Fukusaki E, Rorsman P, Seino S (2014) Glutamate acts as a key signal linking glucose metabolism to incretin/cAMP action to amplify insulin secretion. Cell Rep 9(2):661–673.  https://doi.org/10.1016/j.celrep.2014.09.030 CrossRefPubMedCentralPubMedGoogle Scholar
  30. Gibson J, Russ TC, Adams MJ, Clarke TK, Howard DM, Hall LS, Fernandez-Pujals AM, Wigmore EM, Hayward C, Davies G, Murray AD, Smith BH, Porteous DJ, Deary IJ, McIntosh AM (2017) Assessing the presence of shared genetic architecture between Alzheimer’s disease and major depressive disorder using genome-wide association data. Transl Psychiatry 7(4):e1094.  https://doi.org/10.1038/tp.2017.49 CrossRefPubMedCentralPubMedGoogle Scholar
  31. Gudala K, Bansal D, Schifano F, Bhansali A (2013) Diabetes mellitus and risk of dementia: a meta-analysis of prospective observational studies. J Diabetes Investig 4(6):640–650.  https://doi.org/10.1111/jdi.12087 CrossRefPubMedCentralPubMedGoogle Scholar
  32. Gueli MC, Taibi G (2013) Alzheimer’s disease: amino acid levels and brain metabolic status. Neurol Sci 34(9):1575–1579.  https://doi.org/10.1007/s10072-013-1289-9 CrossRefPubMedGoogle Scholar
  33. Hao K, Di Narzo AF, Ho L et al (2015) Shared genetic etiology underlying Alzheimer’s disease and type 2 diabetes. Mol Asp Med 43–44:66–76.  https://doi.org/10.1016/j.mam.2015.06.006 CrossRefGoogle Scholar
  34. Hardy JA, Higgins GA (1992) Alzheimer’s disease: the amyloid cascade hypothesis. Science (80) 256:184–185Google Scholar
  35. Herrup K (2015) The case for rejecting the amyloid cascade hypothesis. Nat Neurosci 18(6):794–799.  https://doi.org/10.1038/nn.4017 CrossRefPubMedGoogle Scholar
  36. Hollenhorst PC, Chandler KJ, Poulsen RL, Johnson WE, Speck NA, Graves BJ (2009) DNA specificity determinants associate with distinct transcription factor functions. PLoS Genet 5(12):e1000778.  https://doi.org/10.1371/journal.pgen.1000778 CrossRefPubMedCentralPubMedGoogle Scholar
  37. Hoyer S, Nitsch R, Oesterreich K (1990) Ammonia is endogenously generated in the brain in the presence of presumed and verified dementia of Alzheimer type. Neurosci Lett 117(3):358–362.  https://doi.org/10.1016/0304-3940(90)90691-2 CrossRefPubMedGoogle Scholar
  38. Huang X-T, Li C, Peng X-P, Guo J, Yue SJ, Liu W, Zhao FY, Han JZ, Huang YH, Yang-Li, Cheng QM, Zhou ZG, Chen C, Feng DD, Luo ZQ (2017) An excessive increase in glutamate contributes to glucose-toxicity in β-cells via activation of pancreatic NMDA receptors in rodent diabetes. Sci Rep 7:44120.  https://doi.org/10.1038/srep44120 CrossRefPubMedCentralPubMedGoogle Scholar
  39. Inagaki N, Kuromi H, Gonoi T, Okamoto Y, Ishida H, Seino Y, Kaneko T, Iwanaga T, Seino S (1995) Expression and role of ionotropic glutamate receptors in pancreatic islet cells. FASEB 9(8):686–691.  https://doi.org/10.1096/fasebj.9.8.7768362 CrossRefGoogle Scholar
  40. Iwanami J, Mogi M, Tsukuda K, Jing F, Ohshima K, Wang XL, Nakaoka H, Kan-no H, Chisaka T, Bai HY, Min LJ, Horiuchi M (2014) Possible synergistic effect of direct angiotensin II type 2 receptor stimulation by compound 21 with memantine on prevention of cognitive decline in type 2 diabetic mice. Eur J Pharmacol 724:9–15.  https://doi.org/10.1016/j.ejphar.2013.12.015 CrossRefPubMedGoogle Scholar
  41. Janson J, Laedtke T, Parisi JE, et al (2004) Increased risk of type 2 diabetes in Alzheimer diseaseGoogle Scholar
  42. Katon W, Lyles CR, Parker MM, Karter AJ, Huang ES, Whitmer RA (2012) Association of depression with increased risk of dementia in patients with type 2 diabetes. Arch Gen Psychiatry 69(4):410–417.  https://doi.org/10.1001/archgenpsychiatry.2011.154 CrossRefPubMedGoogle Scholar
  43. Klaus V, Vermeulen T, Minassian B, Israelian N, Engel K, Lund AM, Roebrock K, Christensen E, Häberle J (2009) Highly variable clinical phenotype of carbamylphosphate synthetase 1 deficiency in one family: an effect of allelic variation in gene expression? Clin Genet 76(3):263–269.  https://doi.org/10.1111/j.1399-0004.2009.01216.x CrossRefPubMedGoogle Scholar
  44. Kulijewicz-Nawrot M, Syková E, Chvátal A, Verkhratsky A, Rodríguez JJ (2013) Astrocytes and glutamate homoeostasis in Alzheimer’s disease: a decrease in glutamine synthetase, but not in glutamate transporter-1, in the prefrontal cortex. ASN Neuro 5(4):273–282.  https://doi.org/10.1042/AN20130017 CrossRefPubMedGoogle Scholar
  45. Lau A, Tymianski M (2010) Glutamate receptors, neurotoxicity and neurodegeneration. Eur J Phys 460(2):525–542.  https://doi.org/10.1007/s00424-010-0809-1 CrossRefGoogle Scholar
  46. Lee JH, Cheng R, Graff-Radford N, Foroud T, Mayeux R, National Institute on Aging Late-Onset Alzheimer’s Disease Family Study Group (2008) Analyses of the National Institute on Aging Late-Onset Alzheimer’s Disease Family Study: implication of additional loci. Arch Neurol 65(11):1518–1526.  https://doi.org/10.1001/archneur.65.11.1518 CrossRefPubMedCentralPubMedGoogle Scholar
  47. Lee Y, Son H, Kim G, Kim S, Lee DH, Roh GS, Kang SS, Cho GJ, Choi WS, Kim HJ (2013) Glutamine deficiency in the prefrontal cortex increases depressive-like behaviours in male mice. J Psychiatry Neurosci 38(3):183–191.  https://doi.org/10.1503/jpn.120024 CrossRefPubMedCentralPubMedGoogle Scholar
  48. Li X, Song D, Leng SX (2015) Link between type 2 diabetes and Alzheimer’s disease: from epidemiology to mechanism and treatment. Clin Interv Aging 10:549–560.  https://doi.org/10.2147/CIA.S74042 CrossRefPubMedCentralPubMedGoogle Scholar
  49. Litovchick L, Sadasivam S, Florens L, Zhu X, Swanson SK, Velmurugan S, Chen R, Washburn MP, Liu XS, DeCaprio JA (2007) Evolutionarily conserved multisubunit RBL2/p130 and E2F4 protein complex represses human cell cycle-dependent genes in quiescence. Mol Cell 26(4):539–551.  https://doi.org/10.1016/j.molcel.2007.04.015 CrossRefPubMedGoogle Scholar
  50. Liu Z-P, Wu C, Miao H, Wu H (2015) RegNetwork: an integrated database of transcriptional and post-transcriptional regulatory networks in human and mouse. Database 2015:bav095.  https://doi.org/10.1093/database/bav095
  51. Luchsinger JA, Reitz C, Honig LS, Tang MX, Shea S, Mayeux R (2005) Aggregation of vascular risk factors and risk of incident Alzheimer disease. Neurology 65(4):545–551.  https://doi.org/10.1212/01.wnl.0000172914.08967.dc CrossRefPubMedCentralPubMedGoogle Scholar
  52. Marquard J, Otter S, Welters A, Stirban A, Fischer A, Eglinger J, Herebian D, Kletke O, Klemen MS, Stožer A, Wnendt S, Piemonti L, Köhler M, Ferrer J, Thorens B, Schliess F, Rupnik MS, Heise T, Berggren PO, Klöcker N, Meissner T, Mayatepek E, Eberhard D, Kragl M, Lammert E (2015) Characterization of pancreatic NMDA receptors as possible drug targets for diabetes treatment. Nat Med 21(4):363–372.  https://doi.org/10.1038/nm.3822 CrossRefPubMedGoogle Scholar
  53. McGeer EG, McGeer PL, Akiyama H, Harrop R (1989) Cortical glutaminase, beta-glucuronidase and glucose utilization in Alzheimer’s disease. Can J Neurol Sci 16(S4):511–515.  https://doi.org/10.1017/S0317167100029851 CrossRefPubMedGoogle Scholar
  54. Miguel-Hidalgo JJ, Waltzer R, Whittom AA, Austin MC, Rajkowska G, Stockmeier CA (2010) Glial and glutamatergic markers in depression, alcoholism, and their comorbidity. J Affect Disord 127(1-3):230–240.  https://doi.org/10.1016/j.jad.2010.06.003 CrossRefPubMedCentralPubMedGoogle Scholar
  55. Mirza Z, Kamal MA, Buzenadah AM et al (2014) Establishing genomic/transcriptomic links between Alzheimer’s disease and type 2 diabetes mellitus by meta-analysis approach. CNS Neurol Disord Drug Targets 13(3):501–516.  https://doi.org/10.2174/18715273113126660154 CrossRefPubMedGoogle Scholar
  56. Miulli DE, Norwell DY, Schwartz FN (1993) Plasma concentrations of glutamate and its metabolites in patients with Alzheimer’s disease. J Am Osteopath Assoc 93(6):670–676PubMedGoogle Scholar
  57. Myhrer T (1998) Adverse psychological impact, glutamatergic dysfunction, and risk factors for Alzheimer’s disease. Neurosci Biobehav Rev 23(1):131–139.  https://doi.org/10.1016/S0149-7634(98)00039-6 CrossRefPubMedGoogle Scholar
  58. Ott A, Stolk RP, van Harskamp F, Pols HAP, Hofman A, Breteler MMB (1999) Diabetes mellitus and the risk of dementia: the Rotterdam Study. Neurology 53(9):1937–1942.  https://doi.org/10.1212/WNL.53.9.1937 CrossRefPubMedGoogle Scholar
  59. Proitsi P, Lupton MK, Velayudhan L, Hunter G, Newhouse S, Lin K, Fogh I, Tsolaki M, Daniilidou M, Pritchard M, Craig D, Todd S, Johnston JA, McGuinness B, Kloszewska I, Soininen H, Mecocci P, Vellas B, Passmore PA, Sims R, Williams J, Brayne C, Stewart R, Sham P, Lovestone S, Powell JF (2014) Alleles that increase risk for type 2 diabetes mellitus are not associated with increased risk for Alzheimer’s disease. Neurobiol Aging 35:2883.e3–2882883.e10. doi:  https://doi.org/10.1016/j.neurobiolaging.2014.07.023, 12
  60. Prudente S, Shah H, Bailetti D, Pezzolesi M, Buranasupkajorn P, Mercuri L, Mendonca C, de Cosmo S, Niewczas M, Trischitta V, Doria A (2015) Genetic variant at the GLUL locus predicts all-cause mortality in patients with type 2 diabetes. Diabetes 64(7):2658–2663.  https://doi.org/10.2337/db14-1653 CrossRefPubMedCentralPubMedGoogle Scholar
  61. Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MAR, Bender D, Maller J, Sklar P, de Bakker PIW, Daly MJ, Sham PC (2007) PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 81(3):559–575.  https://doi.org/10.1086/519795 CrossRefPubMedCentralPubMedGoogle Scholar
  62. Raabe W (1987) Synaptic transmission in ammonia intoxication. Neurochem Pathol 6(1-2):145–166.  https://doi.org/10.1007/BF02833604 CrossRefPubMedGoogle Scholar
  63. Robinson SR (2000) Neuronal expression of glutamine synthetase in Alzheimer’s disease indicates a profound impairment of metabolic interactions with astrocytes. Neurochem Int 36(4-5):471–482.  https://doi.org/10.1016/S0197-0186(99)00150-3 CrossRefPubMedGoogle Scholar
  64. Rojas J, Teran-Angel G, Barbosa L, Peterson DL, Berrueta L, Salmen S (2016) Activation-dependent mitochondrial translocation of Foxp3 in human hepatocytes. Exp Cell Res 343(2):159–167.  https://doi.org/10.1016/j.yexcr.2016.04.008 CrossRefPubMedGoogle Scholar
  65. Sanacora G, Treccani G, Popoli M (2012) Towards a glutamate hypothesis of depression: an emerging frontier of neuropsychopharmacology for mood disorders. Neuropharmacology 62(1):63–77.  https://doi.org/10.1016/j.neuropharm.2011.07.036 CrossRefPubMedGoogle Scholar
  66. Seiler N (1993) Is ammonia a pathogenetic factor in Alzheimer’s disease? Neurochem Res 18(3):235–245.  https://doi.org/10.1007/BF00969079 CrossRefPubMedGoogle Scholar
  67. Seiler N (2002) Ammonia and Alzheimer’s disease. Neurochem Int 41(2-3):189–207.  https://doi.org/10.1016/S0197-0186(02)00041-4 CrossRefPubMedGoogle Scholar
  68. Suárez I, Bodega G, Fernández B (2002) Glutamine synthetase in brain: effect of ammonia. Neurochem Int 41(2-3):123–142.  https://doi.org/10.1016/S0197-0186(02)00033-5 CrossRefPubMedGoogle Scholar
  69. Sullivan PF, Neale MC, Kendler KS (2000) Genetic epidemiology of major depression: review and meta-analysis. Am J Psychiatry 157:1552–1562.  https://doi.org/10.1176/appi.ajp.157.10.1552
  70. Suzuki Y, Matsushima A, Ohtake A, Mori M, Tatibana M, Orii T (1986) Carbamyl phosphate synthetase I deficiency with no detectable mRNA activity. Eur J Pediatr 145(5):406–408.  https://doi.org/10.1007/BF00439249 CrossRefPubMedGoogle Scholar
  71. Szylberg Ł, Karbownik D, Marszałek A (2016) The role of FOXP3 in human cancers. Anticancer Res 36(8):3789–3794PubMedGoogle Scholar
  72. Tu P-C, Chen L-F, Hsieh J-C, Bai YM, Li CT, Su TP (2012) Regional cortical thinning in patients with major depressive disorder: a surface-based morphometry study. Psychiatry Res Neuroimaging 202(3):206–213.  https://doi.org/10.1016/j.pscychresns.2011.07.011 CrossRefPubMedGoogle Scholar
  73. Uhlén M, Fagerberg L, Hallström BM, et al (2015) Tissue-based map of the human proteomeGoogle Scholar
  74. Vent-Schmidt J, Han JM, MacDonald KG, Levings MK (2014) The role of FOXP3 in regulating immune responses. Int Rev Immunol 33(2):110–128.  https://doi.org/10.3109/08830185.2013.811657 CrossRefPubMedGoogle Scholar
  75. Willemsen G, Ward KJ, Bell CG, et al (2015) The concordance and heritability of type 2 diabetes in 34,166 twin pairs from international twin registers: the Discordant Twin (DISCOTWIN) Consortium. Twin Res Hum Genet 18:762–771.  https://doi.org/10.1017/thg.2015.83
  76. Xu J, Begley P, Church SJ, Patassini S, Hollywood KA, Jüllig M, Curtis MA, Waldvogel HJ, Faull RLM, Unwin RD, Cooper GJS (2016) Graded perturbations of metabolism in multiple regions of human brain in Alzheimer’s disease: snapshot of a pervasive metabolic disorder. Biochim Biophys Acta - Mol Basis Dis 1862(6):1084–1092.  https://doi.org/10.1016/j.bbadis.2016.03.001 CrossRefGoogle Scholar
  77. Yokoi N, Gheni G, Takahashi H, Seino S (2016) β-Cell glutamate signaling: its role in incretin-induced insulin secretion. J Diabetes Investig 7(Suppl 1):38–43.  https://doi.org/10.1111/jdi.12468 CrossRefPubMedCentralPubMedGoogle Scholar
  78. Yoon S, Cho H, Kim J, Lee DW, Kim GH, Hong YS, Moon S, Park S, Lee S, Lee S, Bae S, Simonson DC, Lyoo IK (2017) Brain changes in overweight/obese and normal-weight adults with type 2 diabetes mellitus. Diabetologia 60(7):1–11.  https://doi.org/10.1007/s00125-017-4266-7 CrossRefGoogle Scholar
  79. Zhou Y, Danbolt NC (2014) Glutamate as a neurotransmitter in the healthy brain. J Neural Transm 121(8):799–817.  https://doi.org/10.1007/s00702-014-1180-8 CrossRefPubMedCentralPubMedGoogle Scholar

Copyright information

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

Authors and Affiliations

  • Jeddidiah W. D. Griffin
    • 1
  • Ying Liu
    • 2
  • Patrick C. Bradshaw
    • 1
  • Kesheng Wang
    • 2
  1. 1.Department of Biomedical Sciences, Quillen College of MedicineEast Tennessee State UniversityJohnson CityUSA
  2. 2.Department of Biostatistics and Epidemiology, College of Public HealthEast Tennessee State UniversityJohnson CityUSA

Personalised recommendations