Skip to main content

Mechanisms of l-Serine Neuroprotection in vitro Include ER Proteostasis Regulation

Abstract

β-N-methylamino-l-alanine (L-BMAA) is a neurotoxic non-protein amino acid produced by cyanobacteria. Recently, chronic dietary exposure to l-BMAA was shown to trigger neuropathology in nonhuman primates consistent with Guamanian ALS/PDC, a paralytic disease that afflicts Chamorro villagers who consume traditional food items contaminated with l-BMAA. However, the addition of the naturally occurring amino acid l-serine to the diet of the nonhuman primates resulted in a significant reduction in ALS/PDC neuropathology. l-serine is a dietary amino acid that plays a crucial role in central nervous system development, neuronal signaling, and synaptic plasticity and has been shown to impart neuroprotection from l-BMAA-induced neurotoxicity both in vitro and in vivo. We have previously shown that l-serine prevents the formation of autofluorescent aggregates and death by apoptosis in human cell lines and primary cells. These effects are likely imparted by l-serine blocking incorporation of l-BMAA into proteins hence preventing proteotoxic stress. However, there are likely other mechanisms for l-serine-mediated neuroprotection. Here, we explore the molecular mechanisms of l-serine neuroprotection using a human unfolded protein response real-time PCR array with genes from the ER stress and UPR pathways, and western blotting. We report that l-serine caused the differential expression of many of the same genes as l-BMAA, even though concentrations of l-serine in the culture medium were ten times lower than that of l-BMAA. We propose that l-serine may be functioning as a small proteostasis regulator, in effect altering the cells to quickly respond to a possible oxidative insult, thus favoring a return to homeostasis.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3

Abbreviations

AD:

Alzheimer’s disease

AMPA:

α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid

ALS:

Amyotrophic lateral sclerosis

ALS/PDC:

Amyotrophic lateral sclerosis/parkinsonism-dementia complex

ATF4:

Activating transcription factor 4

ATF6:

Activating transcription factor 6

BCA:

Bicinchoninic acid

l-BMAA:

β-N-methylamino-l-alanine

BiP:

Binding immunoglobulin protein

CHOP:

C/EBP homologous protein

CNS:

Central nervous system

Ct:

Cycle threshold

eIF2:

Eukaryotic initiation factor 2

eIF2α:

Eukaryotic initiation factor 2 subunit alpha

ER:

Endoplasmic reticulum

ERAD:

ER-associated degradation

IRE1:

Inositol-requiring enzyme 1

Grp78:

78 kDa glucose regulating protein

Hsp70:

Heat shock protein 70

NFTs:

Neurofibrillary tangles

PD:

Parkinson’s disease

PDI:

Protein disulfide isomerase

mGluR5:

Metabotropic glutamate receptor 5

NMDA:

N-methyl-d-aspartate receptor

PERK:

Protein kinase RNA-like endoplasmic reticulum kinase

Tg:

Thapsigargin

UPR:

Unfolded protein response

UTC:

Untreated control

XBP1:

X-box binding protein-1

References

Download references

Acknowledgements

This research was supported by the Josephine P. and John J. Louis Foundation. The authors thank Dr. Marnie Peterson for providing the facilities for cell culture.

ORCID numbers: Dunlop RA, 0000-0002-7816-3251; Powell J, 0000-0001-6358-9252; Guillemin GJ, 0000-0001-8105-4470; and Cox PA, 0000-0001-6401-2981.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to P. A. Cox.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Dunlop, R.A., Powell, J., Guillemin, G.J. et al. Mechanisms of l-Serine Neuroprotection in vitro Include ER Proteostasis Regulation. Neurotox Res 33, 123–132 (2018). https://doi.org/10.1007/s12640-017-9829-3

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12640-017-9829-3

Keywords

  • Unfolded protein response
  • ER stress
  • Neuroprotection
  • l-serine
  • l-BMAA