PMID- 25422446 OWN - NLM STAT- MEDLINE DCOM- 20150428 LR - 20220331 IS - 1091-6490 (Electronic) IS - 0027-8424 (Print) IS - 0027-8424 (Linking) VI - 111 IP - 49 DP - 2014 Dec 9 TI - A calcium-dependent protease as a potential therapeutic target for Wolfram syndrome. PG - E5292-301 LID - 10.1073/pnas.1421055111 [doi] AB - 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. FAU - Lu, Simin AU - Lu S AD - Department of Medicine, Division of Endocrinology, Metabolism, and Lipid Research, Washington University School of Medicine, St. Louis, MO 63110; Graduate School of Biomedical Sciences, University of Massachusetts Medical School, Worcester, MA 01655; FAU - Kanekura, Kohsuke AU - Kanekura K AD - Department of Medicine, Division of Endocrinology, Metabolism, and Lipid Research, Washington University School of Medicine, St. Louis, MO 63110; FAU - Hara, Takashi AU - Hara T AD - Department of Medicine, Division of Endocrinology, Metabolism, and Lipid Research, Washington University School of Medicine, St. Louis, MO 63110; FAU - Mahadevan, Jana AU - Mahadevan J AD - Department of Medicine, Division of Endocrinology, Metabolism, and Lipid Research, Washington University School of Medicine, St. Louis, MO 63110; FAU - Spears, Larry D AU - Spears LD AD - Department of Medicine, Division of Endocrinology, Metabolism, and Lipid Research, Washington University School of Medicine, St. Louis, MO 63110; FAU - Oslowski, Christine M AU - Oslowski CM AD - Department of Medicine, Boston University School of Medicine, Boston, MA 02118; FAU - Martinez, Rita AU - Martinez R AD - Department of Genetics, iPSC core facility, Washington University School of Medicine, St. Louis, MO 63110; FAU - Yamazaki-Inoue, Mayu AU - Yamazaki-Inoue M AD - Department of Reproductive Biology, National Center for Child Health and Development, Tokyo 157-8535, Japan; FAU - Toyoda, Masashi AU - Toyoda M AD - Department of Reproductive Biology, National Center for Child Health and Development, Tokyo 157-8535, Japan; FAU - Neilson, Amber AU - Neilson A AD - Department of Genetics, iPSC core facility, Washington University School of Medicine, St. Louis, MO 63110; FAU - Blanner, Patrick AU - Blanner P AD - Department of Genetics, iPSC core facility, Washington University School of Medicine, St. Louis, MO 63110; FAU - Brown, Cris M AU - Brown CM AD - Department of Medicine, Division of Endocrinology, Metabolism, and Lipid Research, Washington University School of Medicine, St. Louis, MO 63110; FAU - Semenkovich, Clay F AU - Semenkovich CF AD - Department of Medicine, Division of Endocrinology, Metabolism, and Lipid Research, Washington University School of Medicine, St. Louis, MO 63110; FAU - Marshall, Bess A AU - Marshall BA AD - Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110; FAU - Hershey, Tamara AU - Hershey T AD - Departments of Psychiatry, Neurology, and Radiology, Washington University School of Medicine, St. Louis, MO 63110; FAU - Umezawa, Akihiro AU - Umezawa A AD - Department of Reproductive Biology, National Center for Child Health and Development, Tokyo 157-8535, Japan; FAU - Greer, Peter A AU - Greer PA AD - Department of Pathology and Molecular Medicine, Queen's University, Division of Cancer Biology and Genetics, Queen's Cancer Research Institute, Kingston, Ontario K7L3N6, Canada; and. FAU - Urano, Fumihiko AU - Urano F AD - Department of Medicine, Division of Endocrinology, Metabolism, and Lipid Research, Washington University School of Medicine, St. Louis, MO 63110; Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110 urano@dom.wustl.edu. LA - eng GR - DK067493/DK/NIDDK NIH HHS/United States GR - R01 DK067493/DK/NIDDK NIH HHS/United States GR - R01 HD070855/HD/NICHD NIH HHS/United States GR - UL1 TR000448/TR/NCATS NIH HHS/United States GR - P60 DK020579/DK/NIDDK NIH HHS/United States GR - P30 DK020579/DK/NIDDK NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20141124 PL - United States TA - Proc Natl Acad Sci U S A JT - Proceedings of the National Academy of Sciences of the United States of America JID - 7505876 RN - 0 (Membrane Proteins) RN - 0 (wolframin protein) RN - EC 3.4.22.- (Calpain) RN - EC 3.4.22.52 (CAPNS1 protein, human) RN - EC 3.4.22.53 (CAPN2 protein, human) RN - F64QU97QCR (Dantrolene) RN - SY7Q814VUP (Calcium) SB - IM MH - Adolescent MH - Adult MH - Animals MH - Calcium/*metabolism MH - Calpain/*metabolism MH - Cell Death MH - Cell Line MH - Child MH - Dantrolene/pharmacology MH - Endoplasmic Reticulum/pathology MH - Female MH - Fibroblasts/metabolism MH - HEK293 Cells MH - Humans MH - Induced Pluripotent Stem Cells/cytology MH - Infant, Newborn MH - Male MH - Membrane Proteins/metabolism MH - Mice MH - Mice, Knockout MH - Mutation MH - Neural Stem Cells/*cytology MH - Protein Binding MH - Rats MH - Wolfram Syndrome/genetics/*therapy PMC - PMC4267371 OTO - NOTNLM OT - Wolfram syndrome OT - diabetes OT - endoplasmic reticulum OT - neurodegeneration OT - treatment COIS- The authors declare no conflict of interest. EDAT- 2014/11/26 06:00 MHDA- 2015/04/29 06:00 PMCR- 2014/11/24 CRDT- 2014/11/26 06:00 PHST- 2014/11/26 06:00 [entrez] PHST- 2014/11/26 06:00 [pubmed] PHST- 2015/04/29 06:00 [medline] PHST- 2014/11/24 00:00 [pmc-release] AID - 1421055111 [pii] AID - 201421055 [pii] AID - 10.1073/pnas.1421055111 [doi] PST - ppublish SO - Proc Natl Acad Sci U S A. 2014 Dec 9;111(49):E5292-301. doi: 10.1073/pnas.1421055111. Epub 2014 Nov 24.