Abstract
In human neuroblastoma cell cultures, non-human primates and human beings, L-serine is neuroprotective, acting through a variety of biochemical and molecular mechanisms. Although L-serine is generally classified as a non-essential amino acid, it is probably more appropriate to term it as a “conditional non-essential amino acid” since, under certain circumstances, vertebrates cannot synthesize it in sufficient quantities to meet necessary cellular demands. L-serine is biosynthesized in the mammalian central nervous system from 3-phosphoglycerate and serves as a precursor for the synthesis of the amino acids glycine and cysteine. Physiologically, it has a variety of roles, perhaps most importantly as a phosphorylation site in proteins. Mutations in the metabolic enzymes that synthesize L-serine have been implicated in various human diseases. Dosing of animals with L-serine and human clinical trials investigating the therapeutic effects of L-serine support the FDA’s determination that L-serine is generally regarded as safe (GRAS); it also appears to be neuroprotective. We here consider the role of L-serine in neurological disorders and its potential as a therapeutic agent.
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Abbreviations
- 3-PGDH:
-
3-phosphoglycerate dehydrogenase
- asc-1, asc-2:
-
Alanine-serine-cysteine transporters 1 or 2
- AD:
-
Alzheimer’s disease
- ALS:
-
Amyotrophic lateral sclerosis
- ALS/PDC:
-
Amyotrophic lateral sclerosis/parkinsonism dementia complex
- ATF4:
-
Activating transcription factor 4
- ATF6:
-
Activating transcription factor 6
- ATG8:
-
Autophagy-related gene 8
- BBB:
-
Blood brain barrier
- L-BMAA:
-
β-N-methylamino-L-alanine
- CNS:
-
Central nervous system
- CSF:
-
Cerebral spinal fluid
- DRG:
-
Dorsal root ganglion
- eIF2α:
-
Eukaryotic initiation factor 2alpha
- ER:
-
Endoplasmic reticulum
- ERAD:
-
Endoplasmic-reticulum-associated protein degradation
- FTLD-MND:
-
Frontotemporal lobar degeneration with motor neuron disease
- FTLD-U:
-
Frontotemporal lobar degeneration with ubiquitinated inclusions
- FTDP:
-
Frontotemporal dementia with parkinsonism
- GluR:
-
Glutamate receptors
- GDP:
-
Guanosine diphosphate
- GCN2:
-
General control nondepressible 2
- GRAS:
-
Generally regarded as safe
- GTP:
-
Guanosine triphosphate
- HRI:
-
Hepatic heme-regulated inhibitor
- Met-tRNAi:
-
Initiator methionyl tRNA
- IRE1:
-
Inositol-requiring enzyme 1
- mRNA:
-
Messenger ribonucleic acid
- tRNA:
-
Transfer ribonucleic acid
- NFTs:
-
Neurofibrillary tangles
- NRF-2:
-
Nuclear factor E2-related factor 2
- PERK:
-
Protein kinase RNA-like endoplasmic reticulum kinase
- PKR:
-
Protein kinase R
- PSAT:
-
Phosphoserine aminotransferase
- PSP:
-
Phosphoserine phosphatase
- Rpt:
-
Proteasome subunit regulatory particle 1
- TDP-43:
-
TAR DNA binding protein of 43 kDa
- UPIs:
-
Ubiquitin-positive inclusions
- UPR:
-
Unfolded protein response
- XBP1:
-
X-box binding protein-1
- XBP1s:
-
Spliced X-box binding protein-1
References
Acuna-Hidalgo R, Schanze D, Kariminejad A et al (2014) Neu-Laxova syndrome is a heterogeneous metabolic disorder caused by defects in enzymes of the L-serine biosynthesis pathway. Am J Hum Genet 95:285–293. https://doi.org/10.1016/j.ajhg.2014.07.012
Artom C, Fishman WH, Morehead RP (1945) The relative toxicity of l- and dl-serine in rats. Proc Soc Exp Biol Med 60:284–287
Benevenga NJ, Harper AE (1967) Alleviation of methionine and homocystine toxicity in the rat. J Nutr 93:44–52
Canu N, Ciotti MT, Pollegioni L (2014) Serine racemase: a key player in apoptosis and necrosis. Front Synaptic Neurosci 6:1–15. https://doi.org/10.3389/fnsyn.2014.00009
Catsman-Berrevoets C, de Klerk J, Huymans J et al (1997) Inborn error of serine biosynthesis, a new phenotype. Eur J Paediatr Neurol 1:A43. https://doi.org/10.1177/135245859800400610
Cheng R, Banack SA (2009) Previous studies underestimate BMAA concentrations in cycad flour. Amyotroph Lateral Scler 10(Suppl 2):41–43. https://doi.org/10.3109/17482960903273528
Cohen P (2002) The origins of protein phosphorylation. Nat Cell Biol 4:E127–E130. https://doi.org/10.1038/ncb0502-e127
Cox PA, Metcalf JS (2017) Traditional food items in Ogimi, Okinawa: L-serine content and the potential for neuroprotection. Curr Nutr Rep 6(1):24–31. https://doi.org/10.1007/s13668-017-0191-0
Cox PA, Banack SA, Murch SJ (2003) Biomagnification of cyanobacterial neurotoxins and neurodegenerative disease among the Chamorro people of Guam. Proc Natl Acad Sci U S A 100:13380–13383. https://doi.org/10.1073/pnas.2235808100
Cox PA, Banack SA, Murch SJ et al (2005) Diverse taxa of cyanobacteria produce beta-N-methylamino-L-alanine, a neurotoxic amino acid. Proc Natl Acad Sci U S A 102:5074–5078. https://doi.org/10.1073/pnas.0501526102
Cox PA, Davis DA, Mash DC, et al (2016) Dietary exposure to an environmental toxin triggers neurofibrillary tangles and amyloid deposits in the brain. Proc R Soc B 283(1823). doi: https://doi.org/10.1098/rspb.2015.2397
de Koning TJ, Klomp LWJ (2004) Serine-deficiency syndromes. Curr Opin Neurol 17:197–204
de Koning TJ, Duran M, Van Maldergem L et al (2002) Congenital microcephaly and seizures due to 3-phosphoglycerate dehydrogenase deficiency: outcome of treatment with amino acids. J Inherit Metab Dis 25:119–125. https://doi.org/10.1023/A:1015624726822
de Koning TJ, Snell K, Duran M et al (2003) L-serine in disease and development. Biochem J 371:653–661. https://doi.org/10.1042/BJ20021785
de Koning T, Klomp L, van Oppen A et al (2004) Prenatal and early postnatal treatment in 3-phosphoglycerate-dehydrogenase deficiency. Lancet 364:2221–2222. https://doi.org/10.1016/S0140-6736(04)17596-X
DeNicola GM, Chen P-H, Mullarky E et al (2015) NRF2 regulates serine biosynthesis in non-small cell lung cancer. Nat Genet 47:1475–1481. https://doi.org/10.1038/ng.3421
Duncan MW (1992) beta-Methylamino-L-alanine (BMAA) and amyotrophic lateral sclerosis-parkinsonism dementia of the western Pacific. Ann N Y Acad Sci 648:161–168
Dunlop RA, Cox PA, Banack SA, Rodgers KJ (2013) The non-protein amino acid BMAA is misincorporated into human proteins in place of L-serine causing protein misfolding and aggregation. PLoS One 8:e75376. https://doi.org/10.1371/journal.pone.0075376
Dunlop RA, Main BJ, Rodgers KJ (2014) The deleterious effects of non-protein amino acids from desert plants on human and animal health. J Arid Environ 112:152–158. https://doi.org/10.1016/j.jaridenv.2014.05.005
Dunlop RA, Powell J, Metcalf JS, et al (2017) L-serine-mediated neuroprotection includes the upregulation of the ER stress chaperone protein disulphide isomerase (PDI). Neurotoxicity Research (in press).
El-Hattab AW (2016) Serine biosynthesis and transport defects. Mol Genet Metab 118:153–159. https://doi.org/10.1016/j.ymgme.2016.04.010
Esterhuizen M, Downing TG (2008) Beta-N-methylamino-L-alanine (BMAA) in novel South African cyanobacterial isolates. Ecotoxicol Environ Saf 71:309–313. https://doi.org/10.1016/j.ecoenv.2008.04.010
Fuchs SA, Berger R, de Koning TJ (2011) D-serine: the right or wrong isoform? Brain Res 1401:104–117. https://doi.org/10.1016/j.brainres.2011.05.039
Furuya S, Watanabe M (2003) Novel neuroglial and glioglial relationships mediated by L-serine metabolism. Arch Histol Cytol 66:109–121. https://doi.org/10.1679/aohc.66.109
Furuya S, Tabata T, Mitoma J et al (2000) L-serine and glycine serve as major astroglia-derived trophic factors for cerebellar Purkinje neurons. Proc Natl Acad Sci U S A 97:11528–11533. https://doi.org/10.1073/pnas.200364497
Furuya S, Yoshida K, Kawakami Y et al (2008) Inactivation of the 3-phosphoglycerate dehydrogenase gene in mice: changes in gene expression and associated regulatory networks resulting from serine deficiency. Funct Integr Genomics 8:235–249. https://doi.org/10.1007/s10142-007-0072-5
Garofalo K, Penno A, Schmidt BP et al (2011) Oral L-serine supplementation reduces production of neurotoxic deoxysphingolipids in mice and humans with hereditary sensory autonomic neuropathy type 1. J Clin Invest 121:4735–4745. https://doi.org/10.1172/JCI57549
Gibson L, Holmgreen SP, Huang DC et al (1996) bcl-w, a novel member of the bcl-2 family, promotes cell survival. Oncogene 13:665–675
Glover WB, Mash DC, Murch SJ (2014) The natural non-protein amino acid N-β-methylamino-L-alanine (BMAA) is incorporated into protein during synthesis. Amino Acids. https://doi.org/10.1007/s00726-014-1812-1
Hardy RW, Tantengco VO, Baumann CA (1960) Effects of amino acids on the excretion of various proteins by the rat. J Nutr 70:438–446
Hart CE, Race V, Achouri Y et al (2007) Phosphoserine aminotransferase deficiency: a novel disorder of the serine biosynthesis pathway. Am J Hum Genet 80:931–937. https://doi.org/10.1086/517888
Hasegawa M, Arai T, Nonaka T et al (2008) Phosphorylated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Ann Neurol 64:60–70. https://doi.org/10.1002/ana.21425
Hirabayashi Y, Furuya S (2008) Roles of l-serine and sphingolipid synthesis in brain development and neuronal survival. Prog Lipid Res 47:188–203. https://doi.org/10.1016/j.plipres.2008.01.003
Hirano A, Zimmerman HM (1962) Alzheimer’s neurofibrillary changes: a topographic study. Arch Neurol 7:227–242
Hirano A, Kurland LT, Krooth RS, Lessell S (1961) Parkinsonism-dementia complex, an endemic disease on the island of Guam. I. Clinical features. Brain 84:642–661
Humphrey SJ, James DE, Mann M (2015) Protein phosphorylation: a major switch mechanism for metabolic regulation. Trends Endocrinol Metab 26:676–687. https://doi.org/10.1016/j.tem.2015.09.013
Hunter T (2012) Why nature chose phosphate to modify proteins. Philos Trans R Soc Lond Ser B Biol Sci 367:2513–2516. https://doi.org/10.1098/rstb.2012.0013
Huttlin EL, Jedrychowski MP, Elias JE et al (2010) A tissue-specific atlas of mouse protein phosphorylation and expression. Cell 143:1174–1189. https://doi.org/10.1016/j.cell.2010.12.001
Iqbal K, Liu F, Gong C-X (2016) Tau and neurodegenerative disease: the story so far. Nat Rev Neurol 12:15–27. https://doi.org/10.1038/nrneurol.2015.225
Jaeken J, Detheux M, Van Maldergem L et al (1996a) 3-Phosphoglycerate dehydrogenase deficiency: an inborn error of serine biosynthesis. Arch Dis Child 74:542–545
Jaeken J, Detheux M, Van Maldergem L et al (1996b) 3-Phosphoglycerate dehydrogenase deficiency and 3-phosphoserine phosphatase deficiency: inborn errors of serine biosynthesis. J Inherit Metab Dis 19:223–226
Kalhan SC, Hanson RW (2012) Resurgence of serine: an often neglected but indispensable amino acid. J Biol Chem 287:19786–19791. https://doi.org/10.1074/jbc.R112.357194
Kasai Y, Tachikawa M, Hirose S et al (2011) Transport systems of serine at the brain barriers and in brain parenchymal cells. J Neurochem 118:304–313. https://doi.org/10.1111/j.1471-4159.2011.07313.x
Kurosawa M, Matsumoto G, Sumikura H et al (2016) Serine 403-phosphorylated p62/SQSTM1 immunoreactivity in inclusions of neurodegenerative diseases. Neurosci Res 103:64–70. https://doi.org/10.1016/j.neures.2015.08.002
Lee A-H, Iwakoshi NN, Glimcher LH (2003) XBP-1 regulates a subset of endoplasmic reticulum resident chaperone genes in the unfolded protein response. Mol Cell Biol 23:7448–7459
Levine TD, Miller RG, Bradley WG et al (2017) Phase I clinical trial of safety of L-serine for ALS patients. Amyotroph Lateral Scler Front Degener 18:107–111. https://doi.org/10.1080/21678421.2016.1221971
Lockart RZ, Eagle H (1959) Requirements for growth of single human cells. Science 129:252–254
Mackenzie IRA, Rademakers R (2008) The role of transactive response DNA-binding protein-43 in amyotrophic lateral sclerosis and frontotemporal dementia. Curr Opin Neurol 21:693–700. https://doi.org/10.1097/WCO.0b013e3283168d1d
Maddocks ODK, Berkers CR, Mason SM et al (2012) Serine starvation induces stress and p53-dependent metabolic remodelling in cancer cells. Nature 493:542–546. https://doi.org/10.1038/nature11743
Mally J, Baranyi M, Vizi ES (1996) Change in the concentrations of amino acids in CSF and serum of patients with essential tremor. J Neural Transm 103:555–560. https://doi.org/10.1007/BF01273153
Murch SJ, Cox PA, Banack SA et al (2004a) Occurrence of beta-methylamino-l-alanine (BMAA) in ALS/PDC patients from Guam. Acta Neurol Scand 110:267–269. https://doi.org/10.1111/j.1600-0404.2004.00320.x
Murch SJ, Cox PA, Banack SA (2004b) A mechanism for slow release of biomagnified cyanobacterial neurotoxins and neurodegenerative disease in Guam. Proc Natl Acad Sci U S A 101:12228–12231. https://doi.org/10.1073/pnas.0404926101
Nelson PT, Alafuzoff I, Bigio EH et al (2012) Correlation of Alzheimer disease neuropathologic changes with cognitive status: a review of the literature. J Neuropathol Exp Neurol 5:362–381. https://doi.org/10.1097/NEN.0b013e31825018f7
Nestler E, Greengard P (1999) Protein phosphorylation is of fundamental importance in biological regulation. In: Siegel GJ, Agranoff BW, Albers RW et al (eds) Basic neurochemistry: molecular, cellular, and medical aspects, 6th edn. Lippincott-Raven, Philadelphia
Neumann M, Sampathu DM, Kwong LK et al (2006) Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 314:130–133. https://doi.org/10.1126/science.1134108
Newman EB, Magasanik B (1963) The relation of serine-glycine metabolism to the formation of single-carbon units. Biochim Biophys Acta 78:437–448. https://doi.org/10.1016/0006-3002(63)90905-3
Nishikawa T (2011) Analysis of free D-serine in mammals and its biological relevance. J Chromatog B 879:3169–3183. https://doi.org/10.1016/j.jchromb.2011.08.030
Pablo J, Banack SA, Cox PA et al (2009) Cyanobacterial neurotoxin BMAA in ALS and Alzheimer’s disease. Acta Neurol Scand 120:216–225. https://doi.org/10.1111/j.1600-0404.2008.01150.x
Perluigi M, Barone E, Di Domenico F, Butterfield DA (2016) Aberrant protein phosphorylation in Alzheimer disease brain disturbs pro-survival and cell death pathways. Biochim Biophys Acta Mol Basis Dis 1862:1871–1882. https://doi.org/10.1016/j.bbadis.2016.07.005
Savoca R, Ziegler U, Sonderegger P (1995) Effects of L-serine on neurons in vitro. J Neurosci Methods 61:159–167
Seibenhener M, Babu J (2004) Sequestosome 1/p62 is a polyubiquitin chain binding protein involved in ubiquitin proteasome degradation. Mol Cell Biol 24:8055–8068. https://doi.org/10.1128/MCB.24.18.8055
Sim W, Yin H, Choi H-S et al (2015) L-serine supplementation attenuates alcoholic fatty liver by enhancing homocysteine metabolism in mice and rats. J Nutr 145:260–267. https://doi.org/10.3945/jn.114.199711
Sonenberg N, Hinnebusch AG (2009) Regulation of translation initiation in eukaryotes: mechanisms and biological targets. Cell 136:731–745. https://doi.org/10.1016/j.cell.2009.01.042
Spencer PS, Nunn PB, Hugon J et al (1987) Guam amyotrophic lateral sclerosis-parkinsonism-dementia linked to a plant excitant neurotoxin. Science 237:517–522
Sun L, Song L, Wan Q et al (2015) cMyc-mediated activation of serine biosynthesis pathway is critical for cancer progression under nutrient deprivation conditions. Cell Res 25:429–444. https://doi.org/10.1038/cr.2015.33
Tabatabaie L, Klomp LWJ, Rubio-Gozalbo ME et al (2011) Expanding the clinical spectrum of 3-phosphoglycerate dehydrogenase deficiency. J Inherit Metab Dis 34:181–184. https://doi.org/10.1007/s10545-010-9249-5
Tanji K, Miki Y, Ozaki T et al (2014) Phosphorylation of serine 349 of p62 in Alzheimer’s disease brain. Acta Neuropathol Commun 2:50. https://doi.org/10.1186/2051-5960-2-50
Toshikuni N, Tsutsumi M, Arisawa T (2014) Clinical differences between alcoholic liver disease and nonalcoholic fatty liver disease. World J Gastroenterol 20:8393–8406. https://doi.org/10.3748/wjg.v20.i26.8393
Trojanowski JQ, Ishihara T, Higuchi M et al (2002) Amyotrophic lateral sclerosis/parkinsonism dementia complex: transgenic mice provide insights into mechanisms underlying a common tauopathy in an ethnic minority on Guam. Exp Neurol 176:1–11. https://doi.org/10.1006/exnr.2002.7940
van der Crabben SN, Verhoeven-Duif NM, Brilstra EH et al (2013) An update on serine deficiency disorders. J Inherit Metab Dis 36:613–619. https://doi.org/10.1007/s10545-013-9592-4
van Onselen R, Cook NA, Phelan RR, Downing TG (2015) Bacteria do not incorporate β-N-methylamino-L-alanine into their proteins. Toxicon 102:55–61. https://doi.org/10.1016/j.toxicon.2015.05.014
Vanhelmont T, Vandebroek T, De Vos A et al (2010) Serine-409 phosphorylation and oxidative damage define aggregation of human protein tau in yeast. FEMS Yeast Res 10:992–1005. https://doi.org/10.1111/j.1567-1364.2010.00662.x
Verleysdonk S, Hamprecht B (2000) Synthesis and release of L-serine by rat astroglia-rich primary cultures. Glia 30:19–26
Wek R, Jiang H, Anthony T (2006) Coping with stress: eIF2 kinases and translational control. Biochem Soc Trans 34:7–11. https://doi.org/10.1042/BST20060007
Wolosker H, Blackshaw S, Snyder SH (1999) Serine racemase: a glial enzyme synthesizing D-serine to regulate glutamate-N-methyl-D-aspartate neurotransmission. Proc Natl Acad Sci U S A 96:13409–13414
Yamamoto K, Sato T, Matsui T et al (2007) Transcriptional induction of mammalian ER quality control proteins is mediated by single or combined action of ATF6α and XBP1. Dev Cell 13:365–376. https://doi.org/10.1016/j.devcel.2007.07.018
Yang W, Hinnebusch AG (1996) Identification of a regulatory subcomplex in the guanine nucleotide exchange factor eIF2B that mediates inhibition by phosphorylated eIF2. Mol Cell Biol 16:6603–6616
Yang M, Vousden KH (2016) Serine and one-carbon metabolism in cancer. Nat Rev Cancer 16:650–662. https://doi.org/10.1038/nrc.2016.81
Yang L, Zhang B, Toku K et al (2000) Improvement of the viability of cultured rat neurons by the non-essential amino acids L-serine and glycine that upregulates expression of the anti-apoptotic gene product Bcl-w. Neurosci Lett 295:97–100. https://doi.org/10.1016/S0304-3940(00)01597-4
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The Institute for Ethnomedicine has applied for patents for the use of L-serine to treat neurodegenerative illness (US 13/683,821).
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Metcalf, J.S., Dunlop, R.A., Powell, J.T. et al. L-Serine: a Naturally-Occurring Amino Acid with Therapeutic Potential. Neurotox Res 33, 213–221 (2018). https://doi.org/10.1007/s12640-017-9814-x
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DOI: https://doi.org/10.1007/s12640-017-9814-x