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.
Abstract
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.
