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Calcium Dependent Regulatory Mechanism in Wolfram Syndrome: A Dissertation

Wolfram syndrome is a genetic disorder characterized by diabetes and neurodegeneration. Two causative genes have been identified so far, WFS1 and WFS2, both encoding endoplasmic reticulum (ER) localized transmembrane proteins. Since WFS1 is involved in the ER stress pathway, Wolfram syndrome is considered an ER disease. Despite the underlying importance of ER dysfunction in Wolfram syndrome, the molecular mechanism linking ER to the death of β cells and neurons has not been elucidated.
The endoplasmic reticulum (ER) is an organelle that forms a network of enclosed sacs and tubes that connect the nuclear membrane and other organelles including Golgi and mitochondria. ER plays critical functions in protein folding, protein transport, lipid metabolism, and calcium regulation. Dysregulation of ER function disrupts normal cell metabolism and activates an array of anti-survival pathways, eventually leading to disease state.
Here we show that calpain is involved in both prototypes of Wolfram syndrome. Calpain 2 activity is negatively regulated by WFS2 protein, and hyper-activation of calpain 2 by WFS2-knockdown leads to cell death. Calpain hyper-activation is also present in WFS1 loss of function cells due to the high cytosolic calcium. Extensive calpain activation exists in the Wolfram syndrome mouse model as well as in patient cells. A compound screen targeting ER homeostasis reveals that dantrolene, a ryanodine receptor inhibitor, can prevent cell death in cell models of Wolfram syndrome. Our results demonstrate that the pathway leading to calpain activation provides potential therapeutic targets for Wolfram syndrome and other ER diseases.

Identiferoai:union.ndltd.org:umassmed.edu/oai:escholarship.umassmed.edu:gsbs_diss-1753
Date09 February 2015
CreatorsLu, Simin
PublishereScholarship@UMassChan
Source SetsUniversity of Massachusetts Medical School
Detected LanguageEnglish
Typetext
Formatapplication/pdf
SourceMorningside Graduate School of Biomedical Sciences Dissertations and Theses
RightsCopyright is held by the author, with all rights reserved.

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