Understanding the Unfolded Protein Response (UPR) Pathway: Insights into Neuropsychiatric Disorders and Therapeutic Potentials

Abstract

The Unfolded Protein Response (UPR) serves as a critical cellular mechanism dedicated to maintaining protein homeostasis, primarily within the endoplasmic reticulum (ER). This pathway diligently responds to a variety of intracellular indicators of ER stress with the objective of reinstating balance by diminishing the accumulation of unfolded proteins, amplifying the ER's folding capacity, and eliminating slow-folding proteins. Prolonged ER stress and UPR irregularities have been linked to a range of neuropsychiatric disorders, including major depressive disorder, bipolar disorder, and schizophrenia. This review offers a comprehensive overview of the UPR pathway, delineating its activation mechanisms and its role in the pathophysiology of neuropsychiatric disorders. It highlights the intricate interplay within the UPR and its profound influence on brain function, synaptic perturbations, and neural developmental processes. Additionally, it explores evolving therapeutic strategies targeting the UPR within the context of these disorders, underscoring the necessity for precision and further research to effective treatments. The research findings presented in this work underscore the promising potential of UPR-focused therapeutic approaches to address the complex landscape of neuropsychiatric disorders, giving rise to optimism for improving outcomes for individuals facing these complex conditions.

Keywords: Endoplasmic reticulum (ER) stress; Neuropsychiatric disorders; Unfolded protein response.

Fig. 1

The impact of altered UPR activation on cellular processes over ER regulation. Altered UPR activation, with its capacity to tightly modify ER regulation, provided valuable insights into the diverse cellular processes governed by the UPR. The functional roles associated with UPR activation encompass: transcriptional upregulation of UPR-related proteins, attenuation of general translation, and enhancement of ER capacity. Furthermore, if the proper restoration of ER function is not achieved, the UPR has the potential to induce cell death.

Fig. 2

Regulation of the UPR and its pathways. The UPR is regulated by three ER stress sensors: PERK, ATF6, and IRE1. Normally, these sensors are inactivated in the ER due to their associations with BiP. UPR activation occurs when BiP dissociates from the ER stress transducers, triggered by high levels of unfolded or misfolded proteins. The pathways are as follows: PERK Pathway: Following BiP dissociation, PERK becomes active through oligomerization and autophosphorylation. p-PERK then phosphorylates eIF2α, reducing ER load by decreasing global protein synthesis. p-eIF2α also preferentially stimulates the translation of ATF4, enhancing the expression of cytoprotective genes, autophagy-related genes, and ERAD-related genes. IRE1 Pathway: IRE1 becomes active after BiP dissociation through oligomerization and autophosphorylation. p-IRE1 splices XBP1 mRNA to generate XBP1s, a transcription factor that stimulates the expression of chaperones and genes involved in ER expansion, ERAD, autophagy, and cytoprotection. p-IRE1 also reduces ER load through mRNA degradation via RIDD. ATF6 Pathway: After BiP dissociation, ATF6 translocates to the Golgi complex, where it is cleaved by the proteases S1P and S2P. ATF6p50 then migrates to the nucleus, stimulating the expression of chaperones, autophagy-related genes, ERAD-related genes, and cytoprotective genes.