Molecular Pathophysiology of Wolfram Syndrome and Endoplasmic Reticulum Stress-associated Pancreatic β-cell Failure.

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Wolfram syndrome, caused by the mutations in the WFS1 gene, is characterized by juvenile onset diabetes mellitus and progressive optic atrophy. In the patient's islets, β-cells are selectively lost. The WFS1 gene encodes an endoplasmic reticulum (ER) membrane-embedded protein (Wolframin). We speculated that wolframin is involved in the ER stress responses. Treatment of MIN6 cells with ER stress-inducible chemical such as thapsigargin or tunicamycin, increased wfs1 mRNA levels. Human WFS1 promoter was activated by treatment of the cells with these reagents when it was examined by the WFS1 gene promoter-luciferase reporter system. In addition, we found increased WFS1 mRNA and protein expression in the mouse insulinoma cells derived from Akita mouse, in which ER stress is induced by the misfolded mutant insulin expression. WFS1 promoter was more active in these Akita mouse-derived β-cells. Collectively, our data suggest that WFS1 expression is induced by ER stress.In Wfs1-/- mice, pancreatic β-cell loss largely depends on their genetic backgrounds. To test the hypothesis that the Wfs1-lacking pancreatic β-cells are more susceptible to ER stress, we crossed Wfs1-/- mice on the C57BL/6J background with agouti lethal yellow (A/Ay) mice, a genetic model of mild obesity/insulin resistance. ER chaperon Bip/GRP78 expression increased in the pancreatic islets of A/Ay mice, suggesting the presence of ER stress due to increased demands of insulin biosynthesis and secretion. Although neither the Wfs1-/- mice or the A/Ay mice on the C57BL/6J background develop overt diabetes, all Wfs1-/- A/Ay mice developed overt diabetes. Pancreatic β-cells markedly reduced in the Wfs1-/- A/Ay mice due to apoptosis. These data suggest that the pancreatic β-cells lacking Wfs1 to be more susceptible to ER stress-induced apoptosis.