We have revealed the mechanisms of cell death in Wolfram syndrome and type 1 diabetes, and our findings will be published in Endocrinology soon. In short, calcium leakage from the endoplasmic reticulum is a common molecular process altered in Wolfram syndrome and type 1 diabetes. We are trying to control this process to develop a novel treatment for Wolfram syndrome. Two more research articles related to this topic are under review.
Endocrinology. 2014. [In press]
Calcium efflux from the endoplasmic reticulum leads to β cell death.
Hara T, Mahadevan J, Kanekura K, Hara M, Lu S, Urano F.
It has been established that intracellular calcium homeostasis is critical for survival and function of pancreatic β cells. However, the role of endoplasmic calcium (ER) calcium homeostasis in β cell survival and death is not clear. Here we show that ER calcium depletion plays a critical role in β cell death. Various pathological conditions associated with β cell death, including ER stress, oxidative stress, palmitate, and chronic high glucose, decreased ER calcium levels and SERCA2b expression, leading to β cell death. Ectopic expression of mutant insulin and genetic ablation of WFS1, a causative gene for Wolfram syndrome, also decreased ER calcium levels and induced β cell death. Hyperactivation of calpain-2, a calcium dependent proapoptotic protease, was detected in β cells undergoing ER calcium depletion. Ectopic expression of SERCA2b, as well as pioglitazone and rapamycin treatment, could prevent calcium efflux from the ER and mitigate β cell death under various stress conditions. Our results reveal a critical role of ER calcium depletion in β cell death and indicate that identification of pathways and chemical compounds restoring ER calcium levels will lead to novel therapeutic modalities and pharmacologic interventions for type 1 and type 2 diabetes and other ER-related diseases including Wolfram syndrome.