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


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.

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Fig. 1
Fig. 2
Fig. 3



Alzheimer’s disease


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


Amyotrophic lateral sclerosis


Amyotrophic lateral sclerosis/parkinsonism-dementia complex


Activating transcription factor 4


Activating transcription factor 6


Bicinchoninic acid




Binding immunoglobulin protein


C/EBP homologous protein


Central nervous system


Cycle threshold


Eukaryotic initiation factor 2


Eukaryotic initiation factor 2 subunit alpha


Endoplasmic reticulum


ER-associated degradation


Inositol-requiring enzyme 1


78 kDa glucose regulating protein


Heat shock protein 70


Neurofibrillary tangles


Parkinson’s disease


Protein disulfide isomerase


Metabotropic glutamate receptor 5


N-methyl-d-aspartate receptor


Protein kinase RNA-like endoplasmic reticulum kinase




Unfolded protein response


Untreated control


X-box binding protein-1


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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.

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Correspondence to P. A. Cox.

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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).

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