title: A calcium-dependent protease as a potential therapeutic target for Wolfram syndrome.
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 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.
authors.affiliation: 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;
authors.forename: Simin
authors.initials: S
authors.lastname: Lu
authors.affiliation: Department of Medicine, Division of Endocrinology, Metabolism, and Lipid Research, Washington University School of Medicine, St. Louis, MO 63110;
authors.forename: Kohsuke
authors.initials: K
authors.lastname: Kanekura
authors.affiliation: Department of Medicine, Division of Endocrinology, Metabolism, and Lipid Research, Washington University School of Medicine, St. Louis, MO 63110;
authors.forename: Takashi
authors.initials: T
authors.lastname: Hara
authors.affiliation: Department of Medicine, Division of Endocrinology, Metabolism, and Lipid Research, Washington University School of Medicine, St. Louis, MO 63110;
authors.forename: Jana
authors.initials: J
authors.lastname: Mahadevan
authors.affiliation: Department of Medicine, Division of Endocrinology, Metabolism, and Lipid Research, Washington University School of Medicine, St. Louis, MO 63110;
authors.forename: Larry D
authors.initials: LD
authors.lastname: Spears
authors.affiliation: Department of Medicine, Boston University School of Medicine, Boston, MA 02118;
authors.forename: Christine M
authors.initials: CM
authors.lastname: Oslowski
authors.affiliation: Department of Genetics, iPSC core facility, Washington University School of Medicine, St. Louis, MO 63110;
authors.forename: Rita
authors.initials: R
authors.lastname: Martinez
authors.affiliation: Department of Reproductive Biology, National Center for Child Health and Development, Tokyo 157-8535, Japan;
authors.forename: Mayu
authors.initials: M
authors.lastname: Yamazaki-Inoue
authors.affiliation: Department of Reproductive Biology, National Center for Child Health and Development, Tokyo 157-8535, Japan;
authors.forename: Masashi
authors.initials: M
authors.lastname: Toyoda
authors.affiliation: Department of Genetics, iPSC core facility, Washington University School of Medicine, St. Louis, MO 63110;
authors.forename: Amber
authors.initials: A
authors.lastname: Neilson
authors.affiliation: Department of Genetics, iPSC core facility, Washington University School of Medicine, St. Louis, MO 63110;
authors.forename: Patrick
authors.initials: P
authors.lastname: Blanner
authors.affiliation: Department of Medicine, Division of Endocrinology, Metabolism, and Lipid Research, Washington University School of Medicine, St. Louis, MO 63110;
authors.forename: Cris M
authors.initials: CM
authors.lastname: Brown
authors.affiliation: Department of Medicine, Division of Endocrinology, Metabolism, and Lipid Research, Washington University School of Medicine, St. Louis, MO 63110;
authors.forename: Clay F
authors.initials: CF
authors.lastname: Semenkovich
authors.affiliation: Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110;
authors.forename: Bess A
authors.initials: BA
authors.lastname: Marshall
authors.affiliation: Departments of Psychiatry, Neurology, and Radiology, Washington University School of Medicine, St. Louis, MO 63110;
authors.forename: Tamara
authors.initials: T
authors.lastname: Hershey
authors.affiliation: Department of Reproductive Biology, National Center for Child Health and Development, Tokyo 157-8535, Japan;
authors.forename: Akihiro
authors.initials: A
authors.lastname: Umezawa
authors.affiliation: 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.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Greer
authors.affiliation: 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.
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Urano
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002154:Calpain / Q000378:metabolism*; D016923:Cell Death; D002460:Cell Line; D002648:Child; D003620:Dantrolene / Q000494:pharmacology; D004721:Endoplasmic Reticulum / Q000473:pathology; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology; D007231:Infant, Newborn; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D058953:Neural Stem Cells / Q000166:cytology*; D011485:Protein Binding; D051381:Rats; D014929:Wolfram Syndrome / Q000235:genetics / Q000628:therapy*
chemical_list: D008565:Membrane Proteins; C114987:wolframin protein; D002154:Calpain; C527669:CAPNS1 protein, human; C569870:CAPN2 protein, human; D003620:Dantrolene; D002118:Calcium
keywords: Wolfram syndrome; diabetes; endoplasmic reticulum; neurodegeneration; treatment