Roles of endoplasmic reticulum stress and activating transcription factors in Alzheimer's disease and Parkinson's disease

Endoplasmic reticulum (ER) is a crucial organelle associated with cellular homeostasis. Accumulation of improperly folded proteins results in ER stress, accompanied by the reaction involving triggering unfolded protein response (UPR). The UPR is mediated through ER membrane-associated sensors, such as protein kinase-like ER kinase (PERK), inositol-requiring transmembrane kinase/endoribonuclease 1α, and activating transcription factor 6 (ATF6). Prolonged stress triggers cell apoptotic reaction, resulting in cell death. Neuronal cells are especially susceptible to protein misfolding. Notably, ER and UPR malfunctions are linked to many neurodegenerative diseases, such as Alzheimer's disease (AD) and Parkinson's disease (PD), delineated by accumulation of misfolded proteins. Notably, ATF family members play key roles in AD and PD pathogenesis. However, the connection between ER stress, UPR, and neuropathology is not yet fully understood. Here, we discuss our present knowledge of the association between ER stress, the UPR, and neurodegeneration in AD and PD. We also discuss the roles of ATF family members in AD and PD pathogenesis. Moreover, we provide a mechanistic clarification of how disease-related molecules affect ER protein homeostasis and explore recent findings that connect the UPR to neuronal plasticity.