L-Serine: a Naturally-Occurring Amino Acid with Therapeutic Potential

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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Fig. 1

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

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Correspondence to P. A. Cox.

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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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Keywords

  • L-serine
  • Alzheimer’s Disease
  • Therapy
  • Neuroprotection
  • ALS
  • Neurodegeneration