Abstract
The unfolded protein response (UPR) is a highly evolutionarily conserved response to endoplasmic reticulum (ER) stress, which functions to return cells to homeostasis or send them into apoptosis, depending on the degree of cellular damage. β-N-methylamino-l-alanine (l-BMAA) has been shown to induce ER stress in a variety of models and has been linked to several types of neurodegenerative disease including Guamanian amyotrophic lateral sclerosis/Parkinsonism dementia complex (ALS/PDC). l-Serine, an amino acid critical for cellular metabolism and neurological signaling, has been shown to be protective against l-BMAA-induced neurotoxicity in both animal and cell culture models. While the mechanisms of l-BMAA neurotoxicity have been well characterized, less is known about l-serine neuroprotection. We recently reported that l-serine and l-BMAA generate similar differential expression profiles in a human ER stress/UPR array, despite l-serine being neuroprotective and L-BMAA being linked to neurodegenerative disease. Here, we further investigate the mechanism(s) of l-serine-induced UPR dysregulation by examining key genes and proteins in the ER stress/UPR pathways. We report that l-serine selectively increased protein disulfide isomerase (PDI) protein translation, an ER chaperone involved in refolding misfolded proteins, suggesting it may be modulating the UPR to favor recovery from ER stress. This constitutes a new mechanism for l-serine-mediated neuroprotection and has implications for its use as a therapy for neurodegenerative illnesses.
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Abbreviations
- 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
- l-BMAA:
-
β-N-methylamino-l-alanine
- BiP:
-
Binding immunoglobulin protein
- CF:
-
Cystic fibrosis
- CFTR:
-
Cystic fibrosis transmembrane conductance regulator
- CHOP:
-
C/EBP homologous protein
- ER:
-
Endoplasmic reticulum
- ERAD:
-
ER-associated degradation
- eIF2α:
-
Eukaryotic translation initiation factor 2α
- IRE1:
-
Inositol-requiring enzyme 1
- Grp78:
-
78 kDa glucose regulating protein
- Grp94:
-
Heat Shock Protein 90 kDa Beta
- NMDA:
-
N-Methyl-d-aspartate
- mGluR5:
-
Metabotropic glutamate receptor 5
- PDI:
-
Protein disulfide isomerase
- PERK:
-
Protein kinase RNA-like endoplasmic reticulum kinase
- PRs:
-
Proteostasis regulators
- ROS:
-
Reactive oxygen species
- UPR:
-
Unfolded protein response
- XBP1:
-
X-box binding protein 1
- XBP1s:
-
Spliced form of X-box binding protein-1
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Acknowledgements
This research was supported by the Josephine P. and John J. Lewis Foundation. The authors thank Dr Marnie Peterson for providing facilities for cell culture.
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Dunlop, R.A., Powell, J.T., Metcalf, J.S. et al. l-Serine-Mediated Neuroprotection Includes the Upregulation of the ER Stress Chaperone Protein Disulfide Isomerase (PDI). Neurotox Res 33, 113–122 (2018). https://doi.org/10.1007/s12640-017-9817-7
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DOI: https://doi.org/10.1007/s12640-017-9817-7