期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2014
卷号：111
期号：49
页码：E5292-E5301
DOI：10.1073/pnas.1421055111
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceWolfram syndrome is an autosomal recessive disorder characterized by juvenile diabetes and neurodegeneration, and is considered a prototype of human endoplasmic reticulum (ER) disease. Wolfram syndrome is caused by loss of function mutations of Wolfram syndrome 1 or Wolfram syndrome 2 genes, which encode transmembrane proteins localized to the ER. Despite its rarity, Wolfram syndrome represents the best human disease model currently available to identify drugs and biomarkers associated with ER health. Furthermore, this syndrome is ideal for studying the mechanisms of ER stress-mediated death of neurons and {beta} cells. Here we report that the pathway leading to calpain activation offers potential drug targets for Wolfram syndrome and substrates for calpain might serve as biomarkers for this syndrome. Wolfram syndrome is a genetic disorder characterized by diabetes and neurodegeneration and considered as an endoplasmic reticulum (ER) disease. Despite the underlying importance of ER dysfunction in Wolfram syndrome and the identification of two causative genes, Wolfram syndrome 1 (WFS1) and Wolfram syndrome 2 (WFS2), a molecular mechanism linking the ER to death of neurons and {beta} cells has not been elucidated. Here we implicate calpain 2 in the mechanism of cell death in Wolfram syndrome. Calpain 2 is negatively regulated by WFS2, and elevated activation of calpain 2 by WFS2-knockdown correlates with cell death. Calpain activation is also induced by high cytosolic calcium mediated by the loss of function of WFS1. Calpain hyperactivation is observed in the WFS1 knockout mouse as well as in neural progenitor cells derived from induced pluripotent stem (iPS) cells of Wolfram syndrome patients. A small-scale small-molecule screen targeting ER calcium homeostasis reveals that dantrolene can prevent cell death in neural progenitor cells derived from Wolfram syndrome iPS cells. Our results demonstrate that calpain and the pathway leading its activation provides potential therapeutic targets for Wolfram syndrome and other ER diseases.
