ABSTRACT
Cardiac arrest and stroke are two leading causes of morbidity and mortality worldwide. Both conditions induce brain ischemia, a decrease or cessation of brain blood low, resulting in neuronal death. Depending on the extent and duration of ischemia, cell death may be immediate (necrosis) or delayed. Delayed neuronal death (DND) after ischemia offers opportunity for intervention to prevent cell death; so-called neuroprotection. It is therefore of signiicant clinical interest to understand DND as a prerequisite to successful neuroprotection. All post-ischemic neurons show a translation arrest (TA), or inhibition of proteins synthesis. Translation arrest is transient in surviving neurons but persists in neurons destined to die by DND. Translation arrest is a marker of the expression of postischemic stress responses, the intrinsic genetic programs possessed by neurons to protect themselves and ameliorate the damage wrought by injuries such as ischemia. Transient TA is a marker of successful and persistent TA indicates unsuccessful execution of neuronal stress responses. We trace the evolution of studies of postischemic TA, with focus on our recent work on mRNA regulation as a contributor to post-ischemic TA, where ribosomes are physically separated from mRNA in post-ischemic neurons in the form of mRNA granules. The phenomenology of mRNA granules in the
context of the molecular biology of mRNA regulation is described. Persistent TA can be linked to a defect in mRNA regulation that precludes the translation of intrinsic neuroprotective genes. The empirical results are abstracted to a nonlinear model of cellular injury that accounts for how injury magnitude determines whether a cell recovers or dies. Though driven by clinical necessity to study brain ischemia, we discover an underlying systems biology that illustrates a complex, nonlinear, networked nanotechnology underlying the binary fate decision of survival or death after cell injury.
