The unfolded protein response (UPR) plays a vital role in maintaining cell homeostasis as a
consequence of endoplasmic reticulum (ER) stress. However, prolonged UPR activity leads to cell
death. This time-dependent dual functionality of the UPR represents the adaptive and cytotoxic pathways
that result from ER stress. Chronic UPR activation in systemic and neurodegenerative diseases
has been identified as an early sign of cellular dyshomeostasis.
The Protein Kinase R-like ER Kinase (PERK) pathway is one of three major branches in the UPR, and
it is the only one to modulate protein synthesis as an adaptive response. The specific identification of prolonged PERK activity
has been correlated with the progression of disorders such as diabetes, Alzheimer’s disease, and cancer, suggesting
that PERK plays a role in the pathology of these disorders. For the first time, the term “PERK-opathies” is used to group
these diseases in which PERK mediates detriment to the cell culminating in chronic disorders. This article reviews the literature
documenting links between systemic disorders with the UPR, but with a specific emphasis on the PERK pathway.
Then, articles reporting links between the UPR, and more specifically PERK, and neurodegenerative disorders are presented.
Finally, a therapeutic perspective is discussed, where PERK interventions could be potential remedies for cellular
dysfunction in chronic neurodegenerative disorders.