GSBS Student Publications

Student Author(s)

Simin Lu

GSBS Program

Interdisciplinary Graduate Program

UMMS Affiliation

Graduate School of Biomedical Sciences

Date

12-9-2014

Document Type

Article

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

Disciplines

Cell Biology | Cellular and Molecular Physiology | Congenital, Hereditary, and Neonatal Diseases and Abnormalities

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.

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

10.1073/pnas.1421055111

Comments

Full author list omitted for brevity. For the full list of authors, see article.

Freely available online through the PNAS open access option.

Related Resources

Link to article in PubMed

Journal Title

Proceedings of the National Academy of Sciences of the United States of America

PubMed ID

25422446

 
 

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