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