Abstract
Homocysteine is a sulfur amino acid that does not occur in the diet, but it is an essential intermediate in normal mammalian metabolism of methionine. Hyperhomocysteinemia results from dietary intakes of Met, folate, and vitamin B12 and lifestyle or from the deficiency of specific enzymes, leading to tissue accumulation of this amino acid and/or its metabolites. Severe hyperhomocysteinemic patients can present neurological symptoms and structural brain abnormalities, of which the pathogenesis is poorly understood. Moreover, a possible link between homocysteine (mild hyperhomocysteinemia) and neurodegenerative/neuropsychiatric disorders has been suggested. In recent years, increasing evidence has emerged suggesting that astrocyte dysfunction is involved in the neurotoxicity of homocysteine and possibly associated with the physiopathology of hyperhomocysteinemia. This review addresses some of the findings obtained from in vivo and in vitro experimental models, indicating high homocysteine levels as an important neurotoxin determinant of the neuropathophysiology of brain damage. Recent data show that this amino acid impairs glutamate uptake, redox/mitochondrial homeostasis, inflammatory response, and cell signaling pathways. Therefore, the discussion of this review focuses on homocysteine-induced gliotoxicity, and its impacts in the brain functions. Through understanding the Hcy-induced gliotoxicity, novel preventive/therapeutic strategies might emerge for these diseases.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Abato JE, Moftah M, Cron GO et al (2020) Methylenetetrahydrofolate reductase deficiency alters cellular response after ischemic stroke in male mice. Nutr Neurosci 1–9 https://doi.org/10.1080/1028415X.2020.1769412
Arús BA, Souza DG, Bellaver B et al (2017) Resveratrol modulates GSH system in C6 astroglial cells through heme oxygenase 1 pathway. Mol Cell Biochem 428:67–77. https://doi.org/10.1007/s11010-016-2917-5
Bélanger M, Allaman I, Magistretti PJ (2011) Brain energy metabolism: focus on astrocyte-neuron metabolic cooperation. Cell Metab 14:724–738. https://doi.org/10.1016/j.cmet.2011.08.016
Bellezza I, Giambanco I, Minelli A, Donato R (2018) Nrf2-Keap1 signaling in oxidative and reductive stress. Biochim Biophys acta Mol cell Res 1865:721–733. https://doi.org/10.1016/j.bbamcr.2018.02.010
Benz B, Grima G, Do KQ (2004) Glutamate-induced homocysteic acid release from astrocytes: possible implication in glia-neuron signaling. Neuroscience 124:377–386. https://doi.org/10.1016/j.neuroscience.2003.08.067
Blaise SA, Nédélec E, Schroeder H et al (2007) Gestational vitamin B deficiency leads to homocysteine-associated brain apoptosis and alters neurobehavioral development in rats. Am J Pathol 170:667–679. https://doi.org/10.2353/ajpath.2007.060339
Bolaños JP (2016) Bioenergetics and redox adaptations of astrocytes to neuronal activity. J Neurochem 139(Suppl):115–125. https://doi.org/10.1111/jnc.13486
Butterfield DA, Halliwell B (2019) Oxidative stress, dysfunctional glucose metabolism and Alzheimer disease. Nat Rev Neurosci 20:148–160. https://doi.org/10.1038/s41583-019-0132-6
Cecchini MS, Bourckhardt GF, Jaramillo ML et al (2019) Exposure to homocysteine leads to cell cycle damage and reactive gliosis in the developing brain. Reprod Toxicol 87:60–69. https://doi.org/10.1016/j.reprotox.2019.05.054
Chamorro Á, Dirnagl U, Urra X, Planas AM (2016) Neuroprotection in acute stroke: targeting excitotoxicity, oxidative and nitrosative stress, and inflammation. Lancet Neurol 15:869–881. https://doi.org/10.1016/S1474-4422(16)00114-9
Chung YH, Hong J-J, Shin CM et al (2003) Immunohistochemical study on the distribution of homocysteine in the central nervous system of transgenic mice expressing a human Cu/Zn SOD mutation. Brain Res 967:226–234. https://doi.org/10.1016/s0006-8993(03)02238-8
Dallérac G, Zapata J, Rouach N (2018) Versatile control of synaptic circuits by astrocytes: where, when and how? Nat Rev Neurosci 19:729–743. https://doi.org/10.1038/s41583-018-0080-6
De Bree A, Verschuren WMM, Kromhout D et al (2002) Homocysteine and coronary heart disease: the importance of a distinction between low and high risk subjects (multiple letters) [1]. Int J Epidemiol 31:1268–1272. https://doi.org/10.1093/ije/31.6.1268
Di Meco A, Li J-G, Barrero C et al (2019) Elevated levels of brain homocysteine directly modulate the pathological phenotype of a mouse model of tauopathy. Mol Psychiatry 24:1696–1706. https://doi.org/10.1038/s41380-018-0062-0
Do KQ, Benz B, Binns KE et al (2004) Release of homocysteic acid from rat thalamus following stimulation of somatosensory afferents in vivo: feasibility of glial participation in synaptic transmission. Neuroscience 124:387–393. https://doi.org/10.1016/j.neuroscience.2003.08.068
Dringen R, Brandmann M, Hohnholt MC, Blumrich E-M (2015) Glutathione-dependent detoxification processes in astrocytes. Neurochem Res 40:2570–2582. https://doi.org/10.1007/s11064-014-1481-1
Dröge W (2002) Free radicals in the physiological control of cell function. Physiol Rev 82:47–95. https://doi.org/10.1152/physrev.00018.2001
Enokido Y, Suzuki E, Iwasawa K et al (2005) Cystathionine β-synthase, a key enzyme for homocysteine metabolism, is preferentially expressed in the radial glia/astrocyte lineage of developing mouse CNS. FASEB J 19:1854–1856. https://doi.org/10.1096/fj.05-3724fje
Ghosh M, Yang Y, Rothstein JD, Robinson MB (2011) Nuclear factor-κB contributes to neuron-dependent induction of glutamate transporter-1 expression in astrocytes. J Neurosci 31:9159–9169. https://doi.org/10.1523/JNEUROSCI.0302-11.2011
Gonçalves C-A, Rodrigues L, Bobermin LD et al (2018) Glycolysis-derived compounds from astrocytes that modulate synaptic communication. Front Neurosci 12:1035. https://doi.org/10.3389/fnins.2018.01035
Greenhalgh AD, David S, Bennett FC (2020) Immune cell regulation of glia during CNS injury and disease. Nat Rev Neurosci 21:139–152. https://doi.org/10.1038/s41583-020-0263-9
Grieve A, Griffiths R (1992) Simultaneous measurement by HPLC of the excitatory amino acid transmitter candidates homocysteate and homocysteine sulphinate supports a predominant astrocytic localisation. Neurosci Lett 145:1–5. https://doi.org/10.1016/0304-3940(92)90189-E
Griffiths R, Grieve A, Dunlop J et al (1989) Inhibition by excitatory sulphur amino acids of the high-affinity L-glutamate transporter in synaptosomes and in primary cultures of cortical astrocytes and cerebellar neurons. Neurochem Res 14:333–343. https://doi.org/10.1007/BF01000036
Guiraud SP, Montoliu I, Da Silva L et al (2017) High-throughput and simultaneous quantitative analysis of homocysteine-methionine cycle metabolites and co-factors in blood plasma and cerebrospinal fluid by isotope dilution LC-MS/MS. Anal Bioanal Chem 409:295–305. https://doi.org/10.1007/s00216-016-0003-1
Halliwell B (2007) Biochemistry of oxidative stress. Biochem Soc Trans 35:1147–1150. https://doi.org/10.1042/BST0351147
Hertz L, Rothman DL (2017) Glutamine-glutamate cycle flux is similar in cultured astrocytes and brain and both glutamate production and oxidation are mainly catalyzed by aspartate aminotransferase Biology (Basel) 6. https://doi.org/10.3390/biology6010017
Hertz L, Zielke HR (2004) Astrocytic control of glutamatergic activity: astrocytes as stars of the show. Trends Neurosci 27:735–743. https://doi.org/10.1016/j.tins.2004.10.008
Huang TC, Lu KT, Wo YYP et al (2011) Resveratrol protects rats from Aβ-induced neurotoxicity by the reduction of iNOS expression and lipid peroxidation. PLoS One 6:e29102. https://doi.org/10.1371/journal.pone.0029102
Illarionova NB, Brismar H, Aperia A, Gunnarson E (2014) Role of Na, K-ATPase α1 and α2 isoforms in the support of astrocyte glutamate uptake. PLoS One 9:e98469. https://doi.org/10.1371/journal.pone.0098469
Jankovic J (2008) Parkinson’s disease: clinical features and diagnosis. J Neurol Neurosurg Psychiatry 79:368–376. https://doi.org/10.1136/jnnp.2007.131045
Jin Y, Amaral A, McCann A, Brennan L (2011) Homocysteine levels impact directly on epigenetic reprogramming in astrocytes. Neurochem Int 58:833–838. https://doi.org/10.1016/j.neuint.2011.03.012
Jin Y, Brennan L (2008) Effects of homocysteine on metabolic pathways in cultured astrocytes. Neurochem Int 52:1410–1415. https://doi.org/10.1016/j.neuint.2008.03.001
Kang CH, Choi YH, Moon SK et al (2013) Quercetin inhibits lipopolysaccharide induced nitric oxide production in BV2 microglial cells by suppressing the NF-κB pathway and activating the Nrf2-dependent HO-1 pathway. Int Immunopharmacol 17:808–813. https://doi.org/10.1016/j.intimp.2013.09.0092013.09.009
Khakh BS, Sofroniew MV (2015) Diversity of astrocyte functions and phenotypes in neural circuits. Nat Neurosci 18:942–952. https://doi.org/10.1038/nn.4043
Kovalska M, Tothova B, Kovalska L et al (2018) Association of induced hyperhomocysteinemia with Alzheimer’s disease-Like neurodegeneration in rat cortical neurons after global ischemia-reperfusion injury. Neurochem Res 43:1766–1778. https://doi.org/10.1007/s11064-018-2592-x
Koz ST, Baydas G, Koz S et al (2012) Gingko biloba extract inhibits oxidative stress and ameliorates impaired glial fibrillary acidic protein expression, but can not improve spatial learning in offspring from hyperhomocysteinemic rat dams. Phytother Res 26:949–955. https://doi.org/10.1002/ptr.3669
Kreft M, Bak LK, Waagepetersen HS, Schousboe A (2012) Aspects of astrocyte energy metabolism, amino acid neurotransmitter homoeostasis and metabolic compartmentation ASN Neuro 4. https://doi.org/10.1042/AN20120007
Kumar M, Sandhir R (2019) Hydrogen sulfide suppresses homocysteine-induced glial activation and inflammatory response. Nitric Oxide - Biol Chem 90:15–28. https://doi.org/10.1016/j.niox.2019.05.008
Langmeier M, Folbergrová J, Haugvicová R et al (2003) Neuronal cell death in hippocampus induced by homocysteic acid in immature rats. Epilepsia 44:299–304. https://doi.org/10.1046/j.1528-1157.2003.31702.x
Lee M, Cho T, Jantaratnotai N et al (2010) Depletion of GSH in glial cells induces neurotoxicity: relevance to aging and degenerative neurological diseases. FASEB J Off Publ Fed Am Soc Exp Biol 24:2533–2545. https://doi.org/10.1096/fj.09-149997
Liddell JR (2017) Are astrocytes the predominant cell type for activation of Nrf2 in aging and neurodegeneration?
Liew SC, Gupta ED (2014) Methylenetetrahydrofolate reductase ( MTHFR ) C677T polymorphism : epidemiology, metabolism and the associated diseases. Eur J Med Genet 58:1–10. https://doi.org/10.1016/j.ejmg.2014.10.004
Lima MC, de Mendonça LR, Rezende AM et al (2019) The transcriptional and protein profile from human infected neuroprogenitor cells is strongly correlated to Zika virus microcephaly cytokines phenotype evidencing a persistent inflammation in the CNS. Front Immunol 10:1928. https://doi.org/10.3389/fimmu.2019.01928
Longoni A, Bellaver B, Bobermin LD et al (2017) Homocysteine induces glial reactivity in adult rat astrocyte cultures. Mol Neurobiol 55:1966–1976. https://doi.org/10.1007/s12035-017-0463-0
Loureiro SO, Heimfarth L, Lacerda BA et al (2010a) Homocysteine induces hypophosphorylation of intermediate filaments and reorganization of actin cytoskeleton in C6 glioma cells. Cell Mol Neurobiol 30:557–568. https://doi.org/10.1007/s10571-009-9480-5
Loureiro SO, Romão L, Alves T et al (2010b) Homocysteine induces cytoskeletal remodeling and production of reactive oxygen species in cultured cortical astrocytes. Brain Res 1355:151–164. https://doi.org/10.1016/j.brainres.2010.07.071
Maler JM, Seifert W, Hüther G et al (2003) Homocysteine induces cell death of rat astrocytes in vitro. Neurosci Lett 347:85–88. https://doi.org/10.1016/s0304-3940(03)00655-4
McBean GJ (2012) The transsulfuration pathway: a source of cysteine for glutathione in astrocytes. Amino Acids 42:199–205. https://doi.org/10.1007/s00726-011-0864-8
Miyamoto R, Otsuguro K, Yamaguchi S, Ito S (2015) Neuronal regulation of expression of hydrogen sulfide-producing enzyme cystathionine β-synthase in rat spinal cord astrocytes. Neurosci Res 97:52–59. https://doi.org/10.1016/j.neures.2015.03.003
Mudd SH (2011) Hypermethioninemias of genetic and non-genetic origin: a review. Am J Med Genet Part C Semin Med Genet 157:3–32. https://doi.org/10.1002/ajmg.c.30293
Navneet S, Zhao J, Wang J et al (2019) Hyperhomocysteinemia-induced death of retinal ganglion cells: the role of Müller glial cells and NRF2. Redox Biol 24:101199. https://doi.org/10.1016/j.redox.2019.101199
Partearroyo T, Pérez-Miguelsanz J, Úbeda N et al (2013) Dietary folic acid intake differentially affects methionine metabolism markers and hippoccampus morphology in aged rats. Eur J Nutr 52:1157–1167. https://doi.org/10.1007/s00394-012-0426-1
Peterson AR, Binder DK (2020) Astrocyte glutamate uptake and signaling as novel targets for antiepileptogenic therapy. Front Neurol 11:1006. https://doi.org/10.3389/fneur.2020.01006
Pierozan P, Biasibetti-Brendler H, Schmitz F et al (2018) Synergistic toxicity of the neurometabolites quinolinic acid and homocysteine in cortical neurons and astrocytes: implications in Alzheimer’s disease. Neurotox Res 34:147–163. https://doi.org/10.1007/s12640-017-9834-6
Pope SAS, Milton R, Heales SJR (2008) Astrocytes protect against copper-catalysed loss of extracellular glutathione. Neurochem Res 33:1410–1418. https://doi.org/10.1007/s11064-008-9602-3
Ravaglia G, Forti P, Maioli F et al (2005) Homocysteine and folate as risk factors for dementia and Alzheimer disease. Am J Clin Nutr 82:636–643. https://doi.org/10.1093/ajcn.82.3.636
Rose J, Brian C, Pappa A et al (2020) Mitochondrial metabolism in astrocytes regulates brain bioenergetics. Neurotransmission and Redox Balance Front Neurosci 14:536682. https://doi.org/10.3389/fnins.2020.536682
Schousboe A, Waagepetersen HS (2005) Role of astrocytes in glutamate homeostasis: implications for excitotoxicity. Neurotox Res 8:221–225. https://doi.org/10.1007/BF03033975
Selhub J (2002) Folate, B12 and B6 and one carbone metabolism. J Nutr Heal Aging 6:39–42
Sharma M, Tiwari M, Tiwari RK (2015) Hyperhomocysteinemia: impact on neurodegenerative diseases. Basic Clin Pharmacol Toxicol 117:287–296. https://doi.org/10.1111/bcpt.12424
Skou JC, Esmann M (1992) The Na, K-ATPase. J Bioenerg Biomembr 24:249–261. https://doi.org/10.1007/BF00768846
Skovierová H, Vidomanová E, Mahmood S et al (2016) The molecular and cellular effect of homocysteine metabolism imbalance on human health. Int J Mol Sci 17:1–18. https://doi.org/10.3390/ijms17101733
Sofroniew MV (2020) Astrocyte reactivity: subtypes, states, and functions in CNS innate immunity. Trends Immunol 41:758–770. https://doi.org/10.1016/j.it.2020.07.004
Sørensen JT, Gaustadnes M, Stabler SP et al (2016) Molecular and biochemical investigations of patients with intermediate or severe hyperhomocysteinemia. Mol Genet Metab 117:344–350. https://doi.org/10.1016/j.ymgme.2015.12.010
Sudduth TL, Weekman EM, Price BR et al (2017) Time-course of glial changes in the hyperhomocysteinemia model of vascular cognitive impairment and dementia (VCID). Neuroscience 341:42–51. https://doi.org/10.1016/j.neuroscience.2016.11.024
Tripathi M, Zhang CW, Singh BK et al (2016) Hyperhomocysteinemia causes ER stress and impaired autophagy that is reversed by Vitamin B supplementation Nat Publ Gr 1–13. https://doi.org/10.1038/cddis.2016.374
Tschopp P, Streit P, Do KQ (1992) Homocysteate and homocysteine sulfinate, excitatory transmitter candidates present in rat astroglial cultures. Neurosci Lett 145:6–9. https://doi.org/10.1016/0304-3940(92)90190-I
Turkes F, Murphy E, Land J et al (2013) Assessment of mitochondrial electron transport chain function in a primary astrocyte cell model of hyperhomocystinaemia. Toxicol Mech Methods 23:459–463. https://doi.org/10.3109/15376516.2013.780276
Verkhratsky A, Parpura V, Vardjan N, Zorec R (2019) Physiology of astroglia. Adv Exp Med Biol 1175:45–91. https://doi.org/10.1007/978-981-13-9913-8_3
Vitvitsky V, Thomas M, Ghorpade A, et al (2006) A functional transsulfuration pathway in the brain links to glutathione homeostasis *. 281:35785–35793. https://doi.org/10.1074/jbc.M602799200
Weekman EM, Sudduth TL, Price BR et al (2019) Time course of neuropathological events in hyperhomocysteinemic amyloid depositing mice reveals early neuroinflammatory changes that precede amyloid changes and cerebrovascular events. J Neuroinflammation 16:284. https://doi.org/10.1186/s12974-019-1685-z
Weekman EM, Woolums AE, Sudduth TL, Wilcock DM (2017) Hyperhomocysteinemia-induced gene expression changes in the cell types of the brain. ASN Neuro 9(6) 1759091417742296. https://doi.org/10.1177/1759091417742296
Yin C, Chan T, Wing S, Cheng K (2017). Elevated homocysteine in human abdominal aortic aneurysmal tissues. https://doi.org/10.1177/1358863X17718260
Zhang X, Chen S, Li L et al (2008) Folic acid protects motor neurons against the increased homocysteine, inflammation and apoptosis in SOD1 G93A transgenic mice. Neuropharmacology 54:1112–1119. https://doi.org/10.1016/j.neuropharm.2008.02.020
Zhou Y, Danbolt NC (2013) GABA and glutamate transporters in brain. Front Endocrinol (Lausanne) 4:165. https://doi.org/10.3389/fendo.2013.00165
Acknowledgements
The authors are supported by Universidade Federal do Rio Grande do Sul (UFRGS), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), and Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul (FAPERGS).
Author information
Authors and Affiliations
Contributions
ATSW, TMS, LDB, and AQS conceived, wrote, and revised the manuscript. TMS and LDB designed and created the figures.
Corresponding author
Ethics declarations
Conflict of Interest
The authors declare no competing interests.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Wyse, A.T.S., Bobermin, L.D., dos Santos, T.M. et al. Homocysteine and Gliotoxicity. Neurotox Res 39, 966–974 (2021). https://doi.org/10.1007/s12640-021-00359-5
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12640-021-00359-5