The functions of IRE1α in neurodegenerative diseases: Beyond ER stress

Inositol-requiring enzyme 1 alpha (IRE1 alpha) is a type I transmembrane protein that resides in the endoplasmic retic-ulum (ER). IRE1 alpha, which is the primary sensor of ER stress, has been proven to maintain intracellular protein homeostasis by activating X-box binding protein 1 (XBP1). Further studies have revealed novel physiological functions of the IRE1 alpha, such as its roles in mRNA and protein degradation, inflammation, immunity, cell pro-liferation and cell death. Therefore, the function of IRE1 alpha is not limited to its role in ER stress; IRE1 alpha is also important for regulating other processes related to cellular physiology. Furthermore, IRE1 alpha plays a key role in neurodegenerative diseases that are caused by the phosphorylation of Tau protein, the accumulation of alpha-syn-uclein (alpha-syn) and the toxic effects of mutant Huntingtin (mHtt). Therefore, targeting IRE1 alpha is a valuable approach for treating neurodegenerative diseases and regulating cell functions. This review discusses the role of IRE1 alpha in different cellular processes, and emphasizes the importance of IRE1 alpha in neurodegenerative diseases.