EBioMedicine | |
Hypothermic Preconditioning of Human Cortical Neurons Requires Proteostatic Priming | |
Bhuvaneish Thangaraj Selvaraj1  Nina Marie Rzechorzek1  Siddharthan Chandran1  Peter Connick1  Rickie Patani2  | |
[1] 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; | |
关键词: Endoplasmic reticulum stress; Unfolded protein response; Hypothermia; Preconditioning; Proteostasis; Neuroprotection; | |
DOI : 10.1016/j.ebiom.2015.04.004 | |
来源: DOAJ |
【 摘 要 】
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.
【 授权许可】
Unknown