Hypothermic Preconditioning of Human Cortical Neurons Requires Proteostatic Priming.
Hypothermia is potently neuroprotective but poor mechanistic understanding has restricted its clinical use. Rodent studies indicate that hypothermia can elicit preconditioning, wherein a subtoxic cellular stress confers resistance to an otherwise lethal injury. The molecular basis of this preconditioning remains obscure. Here we explore molecular effects of cooling using functional cortical neurons differentiated from human pluripotent stem cells (hCNs). Mild-to-moderate hypothermia (28-32 °C) induces cold-shock protein expression and mild endoplasmic reticulum (ER) stress in hCNs, with full activation of the unfolded protein response (UPR). Chemical block of a principal UPR pathway mitigates the protective effect of cooling against oxidative stress, whilst pre-cooling neurons abrogates the toxic injury produced by the ER stressor tunicamycin. Cold-stress thus preconditions neurons by upregulating adaptive chaperone-driven pathways of the UPR in a manner that precipitates ER-hormesis. Our findings establish a novel arm of neurocryobiology that could reveal multiple therapeutic targets for acute and chronic neuronal injury.
Centre for Clinical Brain Sciences, University of Edinburgh, Midlothian EH16 4SB, United Kingdom ; MRC Centre for Regenerative Medicine, University of Edinburgh, Midlothian EH16 4SB, United Kingdom.
Nina Marie
NM
Rzechorzek
Centre for Clinical Brain Sciences, University of Edinburgh, Midlothian EH16 4SB, United Kingdom ; The Anne Rowling Regenerative Neurology Clinic, University of Edinburgh, Midlothian EH16 4SB, United Kingdom.
Peter
P
Connick
The Anne Rowling Regenerative Neurology Clinic, University of Edinburgh, Midlothian EH16 4SB, United Kingdom ; Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London WC1N 3BG, United Kingdom.
Rickie
R
Patani
Centre for Clinical Brain Sciences, University of Edinburgh, Midlothian EH16 4SB, United Kingdom ; MRC Centre for Regenerative Medicine, University of Edinburgh, Midlothian EH16 4SB, United Kingdom.
Bhuvaneish Thangaraj
BT
Selvaraj
Centre for Clinical Brain Sciences, University of Edinburgh, Midlothian EH16 4SB, United Kingdom ; MRC Centre for Regenerative Medicine, University of Edinburgh, Midlothian EH16 4SB, United Kingdom ; The Anne Rowling Regenerative Neurology Clinic, University of Edinburgh, Midlothian EH16 4SB, United Kingdom.
Siddharthan
S
Chandran
D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology*; D058639:Cold-Shock Response / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000235:genetics; D004721:Endoplasmic Reticulum / Q000473:pathology; D059865:Endoplasmic Reticulum Stress / Q000502:physiology*; D006801:Humans; D007036:Hypothermia, Induced / Q000379:methods*; D009474:Neurons / Q000166:cytology* / Q000378:metabolism; D000066829:Neuroprotection / Q000502:physiology; D018384:Oxidative Stress / Q000502:physiology; D039904:Pluripotent Stem Cells / Q000166:cytology; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors / Q000235:genetics; D014415:Tunicamycin / Q000494:pharmacology; D056811:Unfolded Protein Response / Q000502:physiology
D004268:DNA-Binding Proteins; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D014415:Tunicamycin
Endoplasmic reticulum stress; Hypothermia; Neuroprotection; Preconditioning; Proteostasis; Unfolded protein response