Interdisciplinary Graduate Program
Graduate School of Biomedical Sciences
Medical Subject Headings
Adolescent; Adult; Animals; Calcium; Calpain; Cell Death; Cell Line; Child; Dantrolene; Endoplasmic Reticulum; Female; Fibroblasts; HEK293 Cells; Humans; Induced Pluripotent Stem Cells; Infant, Newborn; Male; Membrane Proteins; Mice; Mice, Knockout; Mutation; Neural Stem Cells; Protein Binding; Rats; Wolfram Syndrome
Cell Biology | Cellular and Molecular Physiology | Congenital, Hereditary, and Neonatal Diseases and Abnormalities
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 β 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.
Rights and Permissions
Citation: Lu S, Kanekura K, Hara T, Mahadevan J, Spears LD, Oslowski CM, Martinez R, Yamazaki-Inoue M, Toyoda M, Neilson A, Blanner P, Brown CM, Semenkovich CF, Marshall BA, Hershey T, Umezawa A, Greer PA, Urano F. A calcium-dependent protease as a potential therapeutic target for Wolfram syndrome. Proc Natl Acad Sci U S A. 2014 Dec 9;111(49):E5292-301. doi: 10.1073/pnas.1421055111. Epub 2014 Nov 24. PubMed PMID: 25422446; PubMed Central PMCID: PMC4267371. Link to article on publisher's website
DOI of Published Version
Proceedings of the National Academy of Sciences of the United States of America
Lu, Simin; Semenkovich, Clay F.; Greer, Peter A.; and Urano, Fumihiko, "A calcium-dependent protease as a potential therapeutic target for Wolfram syndrome" (2014). GSBS Student Publications. 1871.