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Proc Natl Acad Sci U S A. 2014 Dec 9;111(49):E5292-301. doi: 10.1073/pnas.1421055111. Epub 2014 Nov 24.

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

Author information

1
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;
2
Department of Medicine, Division of Endocrinology, Metabolism, and Lipid Research, Washington University School of Medicine, St. Louis, MO 63110;
3
Department of Medicine, Boston University School of Medicine, Boston, MA 02118;
4
Department of Genetics, iPSC core facility, Washington University School of Medicine, St. Louis, MO 63110;
5
Department of Reproductive Biology, National Center for Child Health and Development, Tokyo 157-8535, Japan;
6
Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110;
7
Departments of Psychiatry, Neurology, and Radiology, Washington University School of Medicine, St. Louis, MO 63110;
8
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.
9
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.

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.

KEYWORDS:

Wolfram syndrome; diabetes; endoplasmic reticulum; neurodegeneration; treatment

PMID:
25422446
PMCID:
PMC4267371
DOI:
10.1073/pnas.1421055111
[Indexed for MEDLINE]
Free PMC Article

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