Neurotoxicity Research

, Volume 33, Issue 1, pp 123–132 | Cite as

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

  • R. A. Dunlop
  • J. Powell
  • G. J. Guillemin
  • P. A. Cox
ORIGINAL ARTICLE

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.

Keywords

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

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

Notes

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.

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Copyright information

© Springer Science+Business Media, LLC 2017

Authors and Affiliations

  • R. A. Dunlop
    • 1
    • 2
  • J. Powell
    • 1
  • G. J. Guillemin
    • 2
  • P. A. Cox
    • 1
  1. 1.Brain Chemistry LabsThe Institute for EthnomedicineJacksonUSA
  2. 2.Neuroinflammation Group, Faculty of Medicine and Health SciencesMacquarie UniversitySydneyAustralia

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