| dc.description.abstract | Hypothermia is potently neuroprotective, but the molecular basis of this effect
remains obscure and the practical challenges of cooling have restricted its clinical
use. This thesis was borne on the premise that considerable therapeutic potential
may lie in a deeper understanding of the neuronal physiology of cooling. Rodent
studies indicate that hypothermia can elicit preconditioning wherein a subtoxic stress
confers resistance to an otherwise lethal injury. This cooling-induced tolerance
requires de novo protein synthesis – a fundamental arm of the cold-shock response,
for which data in human neurons is lacking. Since cooling protects the human
neonatal brain, experiments herein address the molecular effects of clinicallyrelevant
cooling using functional, maturationally-comparable cortical neurons
differentiated from human pluripotent stem cells (hCNs). Several core hypothermic
phenomena are explored, with particular scrutiny of neuronal tau, since this protein is
modified extensively in brains that are resistant to injury. Mild-to-moderate
hypothermia produces an archetypal cold-shock response in hCNs and protects them
from oxidative and excitotoxic stress. Principal features of human cortical tau
development are recapitulated during hCN differentiation, and subsequently reversed
by cooling, returning tau transcriptionally and post-translationally to an earlier foetallike
state. These findings provide the first evidence of cold-stress-mediated
ontogenic reversal in human neurons. Furthermore, neuroprotective hypothermia
induces mild endoplasmic reticulum (ER) stress in hCNs, with subsequent activation
of the unfolded protein response (UPR). Reciprocal modulation of both tau
phosphorylation and the ER-UPR cascade suggests that cold-induced
hyperphosphorylation of tau and ER-hormesis (preconditioning) represent significant components of hypothermic neuroprotection. Cooling thus modifies proteostatic
pathways in a manner that supports neuronal viability. Historically, hypothermic
preconditioning has been limited to the acute injury setting, and tau
hyperphosphorylation is an established hallmark of chronic neural demise. More
recently however, preconditioning has been proposed as a target for
neurodegenerative disease and neuroprotective roles of phospho-tau have emerged.
To date, hypothermia has protected hCNs against oxidative, excitotoxic and ER
stress, all of which have been implicated in traumatic as well as degenerative
processes. This ‘cross-tolerance’ effect places exponential value on the molecular
neurobiology of cooling, with the potential to extract multiple therapeutic targets for
an unmet need. | en |
