Dual Role of Inositol-requiring Enzyme 1α-X-box Binding protein 1 Signaling in Neurodegenerative Diseases

Abstract

The prevalence of neurodegenerative disease has increased as an outcome of the aging population, and effective clinical treatments for such diseases are lacking. Endoplasmic reticulum dysfunction has been identified as a causative factor in various neurological disorders. The inositol-requiring enzyme 1α (IRE1α)-X-box binding protein 1 (XBP1) signaling pathway is the most conserved branch of the unfolded protein response, functioning in both physiological and pathological processes. The modulation of IRE1α-XBP1 signaling via genetic manipulation or drug administration has opposite effects in multiple disease models of neurodegeneration, indicating the complex and heterogeneous role of IRE1α-XBP1 signaling among neurodegenerative diseases and even at different stages within the same disease. Herein, we focus on the multifaceted nature of IRE1α-XBP1 signaling and provide a detailed overview of the latest findings regarding its biological relevance in brain physiology and neurodegenerative disease pathobiology. Moreover, the possible pharmacological targets in the IRE1α-XBP1 axis are discussed.

Keywords: Autophagy; Calcium; IRE1α; Neurodegeneration; Neuroinflammation; Unfolded protein response; XBP1.