The physiological role of the unfolded protein response in the nervous system

Abstract The unfolded protein response (UPR) is a cellular stress response pathway activated when the endoplasmic reticulum, a crucial organelle for protein folding and modification, encounters an accumulation of unfolded or misfolded proteins. The UPR aims to restore endoplasmic reticulum homeostasis by enhancing protein folding capacity, reducing protein biosynthesis, and promoting protein degradation. It also plays a pivotal role in coordinating signaling cascades to determine cell fate and function in response to endoplasmic reticulum stress. Recent research has highlighted the significance of the UPR not only in maintaining endoplasmic reticulum homeostasis but also in influencing various physiological processes in the nervous system. Here, we provide an overview of recent findings that underscore the UPR’s involvement in preserving the function and viability of neuronal and myelinating cells under physiological conditions, and highlight the critical role of the UPR in brain development, memory storage, retinal cone development, myelination, and maintenance of myelin thickness.