Function of WFS1 and WFS2 in the Central Nervous System: Implications for Wolfram Syndrome and Alzheimer's disease

Abstract

L.P. Li, L. Venkataraman, S. Chen, and H.J. Fu. Function of WFS1 and WFS2 in the Central Nervous System: Implications for Wolfram Syndrome and Alzheimer's Disease. NEUROSCI BIOBEHAV REVXXX-XXX,2020.-Wolfram syndrome (WS) is a rare monogenetic spectrum disorder characterized by insulin-dependent juvenile-onset diabetes mellitus, diabetes insipidus, optic nerve atrophy, hearing loss, progressive neurodegeneration, and a wide spectrum of psychiatric manifestations. Most WS patients belong to Wolfram Syndrome type 1 (WS1) caused by mutations in the Wolfram Syndrome 1 (WFS1/Wolframin) gene, while a small fraction of patients belongs to Wolfram Syndrome type 2 (WS2) caused by pathogenic variants in the CDGSH Iron Sulfur Domain 2 (CISD2/WFS2) gene. Although currently there is no treatment for this life-threatening disease, the molecular mechanisms underlying the pathogenesis of WS have been proposed. Interestingly, Alzheimer's disease (AD), an age-dependent neurodegenerative disease, shares some common mechanisms with WS. In this review, we focus on the function of WFS1 and WFS2 in the central nervous system as well as their implications in WS and AD. We also propose three future directions for elucidating the role of WFS1 and WFS2 in WS and AD.

Keywords: Alzheimer’s disease; Cisd2; ER stress; Excitotoxicity; Mitochondria; Mitophagy; Unfolded protein response; Wfs1; Wfs2; Wolfram Syndrome; Wolframin.