Neurotoxicity Research

, Volume 33, Issue 1, pp 113–122 | Cite as

l-Serine-Mediated Neuroprotection Includes the Upregulation of the ER Stress Chaperone Protein Disulfide Isomerase (PDI)

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

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.

Keywords

Unfolded protein response ER stress Neuroprotection l-Serine l-BMAA PDI 

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

Notes

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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Copyright information

© Springer Science+Business Media, LLC 2017

Authors and Affiliations

  • R. A. Dunlop
    • 1
    • 2
  • J. T. Powell
    • 1
  • J. S. Metcalf
    • 1
  • G. J. Guillemin
    • 2
  • P. A. Cox
    • 1
  1. 1.Brain Chemistry LabsInstitute for EthnomedicineJackson HoleUSA
  2. 2.Neuroinflammation Group, MND and Neurodegenerative Diseases Research CenterMacquarie UniversitySydneyAustralia

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