A calcium-dependent protease as a potential therapeutic target for Wolfram syndrome

Simin Lu, Kohsuke Kanekura, Takashi Hara, Jana Mahadevan, Larry D. Spears, Christine M. Oslowski, Rita Martinez, Mayu Yamazaki-Inoue, Masashi Toyoda, Amber Neilson, Patrick Blanner, Cris M. Brown, Clay F. Semenkovich, Bess A. Marshall, Tamara Hershey, Akihiro Umezawa, Peter A. Greer, Fumihiko Urano

Research output: Contribution to journalArticle

67 Scopus citations

Abstract

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 innodatabeta 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.

Original languageEnglish
Pages (from-to)E5292-E5301
JournalProceedings of the National Academy of Sciences of the United States of America
Volume111
Issue number49
DOIs
StatePublished - Dec 9 2014

Keywords

  • Diabetes
  • Endoplasmic reticulum
  • Neurodegeneration
  • Treatment
  • Wolfram syndrome

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    Lu, S., Kanekura, K., Hara, T., Mahadevan, J., Spears, L. D., Oslowski, C. M., Martinez, R., Yamazaki-Inoue, M., Toyoda, M., Neilson, A., Blanner, P., Brown, C. M., Semenkovich, C. F., Marshall, B. A., Hershey, T., Umezawa, A., Greer, P. A., & Urano, F. (2014). A calcium-dependent protease as a potential therapeutic target for Wolfram syndrome. Proceedings of the National Academy of Sciences of the United States of America, 111(49), E5292-E5301. https://doi.org/10.1073/pnas.1421055111