β-cell dysfunction due to increased ER stress in a stem cell model of Wolfram syndrome.
Wolfram syndrome is an autosomal recessive disorder caused by mutations in WFS1 and is characterized by insulin-dependent diabetes mellitus, optic atrophy, and deafness. To investigate the cause of β-cell failure, we used induced pluripotent stem cells to create insulin-producing cells from individuals with Wolfram syndrome. WFS1-deficient β-cells showed increased levels of endoplasmic reticulum (ER) stress molecules and decreased insulin content. Upon exposure to experimental ER stress, Wolfram β-cells showed impaired insulin processing and failed to increase insulin secretion in response to glucose and other secretagogues. Importantly, 4-phenyl butyric acid, a chemical protein folding and trafficking chaperone, restored normal insulin synthesis and the ability to upregulate insulin secretion. These studies show that ER stress plays a central role in β-cell failure in Wolfram syndrome and indicate that chemical chaperones might have therapeutic relevance under conditions of ER stress in Wolfram syndrome and other forms of diabetes.
The New York Stem Cell Foundation Research Institute, New York, NY.
Linshan
L
Shang
Haiqing
H
Hua
Kylie
K
Foo
Hector
H
Martinez
Kazuhisa
K
Watanabe
Matthew
M
Zimmer
David J
DJ
Kahler
Matthew
M
Freeby
Wendy
W
Chung
Charles
C
LeDuc
Robin
R
Goland
Rudolph L
RL
Leibel
Dieter
D
Egli
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002454:Cell Differentiation; D059865:Endoplasmic Reticulum Stress; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology*; D007328:Insulin / Q000096:biosynthesis / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000502:physiology*; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D010654:Phenylbutyrates / Q000494:pharmacology; D014929:Wolfram Syndrome / Q000235:genetics / Q000473:pathology*
D007328:Insulin; D008565:Membrane Proteins; D010654:Phenylbutyrates; C114987:wolframin protein; C075773:4-phenylbutyric acid; D002118:Calcium