Using temporal genetic switches to synchronize the unfolded protein response in cell populations in vivo

In recent years, recognition of the importance of protein aggregation in human diseases has increasingly come to the fore and it is clear that many degenerative disorders involve activation of a metabolic signaling cascade known as the unfolded protein response (UPR). The UPR encompasses conserved mechanisms in cells to monitor and react to changes in metabolic flux through the secretory pathway. Such changes reflect an imbalance in cell homeostasis and the UPR integrates several signaling cascades to restore homeostasis. As such, the UPR is simply interpreted as a protection mechanism for cells as they perform their normal functions. A number of groups have suggested that the UPR also can eliminate cells in which homeostasis is lost, for example, during disease. This notion has kindled the rather paradoxical concept that inhibiting the UPR will ameliorate degenerative disease. However, several in vivo studies in the nervous system indicate that curtailing UPR function either exacerbates disease or may reduce severity through unexpected or unidentified pathways. Perhaps the notion that the UPR protects cells or eliminates them stems from widespread use of suboptimal paradigms to characterize the UPR; thus, too little is currently known about this homeostatic pathway. Herein, I describe the development of genetic switch technology (GST) to generate a novel model for studying UPR diseases. The model is geared toward obtaining high resolution in vivo detail for oligodendrocytes of the central nervous system, but it can be adapted to study other cell types and other UPR diseases.