In brain, it results in delayed neuronal development and impaired neuronal survival. In beta cells, WFS1 deficiency impairs insulin synthesis and secretion and induces apoptosis. When prolonged, it can lead to cell dysfunction and death. The ER stress response is an adaptive process aiming to restore ER homeostasis.
WFS1 deficiency perturbs ER Ca 2+ homeostasis and causes ER stress, defined as an imbalance between the protein load in the ER and the organelle’s functional capacity. The ER is an essential organelle for pancreatic beta cells and neurons. There are currently no treatments to prevent or delay the disease. People with Wolfram syndrome can also develop cerebellar ataxia, gait and balance abnormalities, memory loss and psychiatric manifestations. In the first two decades of life, individuals affected by Wolfram syndrome develop insulin-dependent diabetes mellitus, optic nerve atrophy, diabetes insipidus and hearing loss. It is caused by mutations in the WFS1 gene which encodes for the endoplasmic reticulum (ER) transmembrane protein WFS1, also called wolframin. Wolfram syndrome is a rare autosomal recessive disorder with a prevalence of one in 700,000 individuals. Our study provides novel evidence for the beneficial effect of GLP-1R agonists on WFS1-deficient human pancreatic beta cells and neurons, suggesting that these drugs may be considered as a treatment for individuals with Wolfram syndrome. Exenatide improved mitochondrial function, reduced oxidative stress and prevented apoptosis in Wolfram syndrome iPSC-derived neural precursors and cerebellar neurons.
Our study shows that the long-lasting GLP-1R agonist dulaglutide reverses impaired glucose tolerance in WFS1-deficient mice, and that exenatide and dulaglutide improve beta cell function and prevent apoptosis in different human WFS1-deficient models including iPSC-derived beta cells from people with Wolfram syndrome. The effect of the GLP-1R agonists dulaglutide and exenatide was examined in Wfs1 knockout mice and in an array of human preclinical models of Wolfram syndrome, including WFS1-deficient human beta cells, human induced pluripotent stem cell (iPSC)-derived beta-like cells and neurons from control individuals and individuals affected by Wolfram syndrome, and humanised mice. Considering the unmet treatment need for this orphan disease, this study aimed to evaluate the therapeutic potential of glucagon-like peptide 1 receptor (GLP-1R) agonists under wolframin (WFS1) deficiency with a particular focus on human beta cells and neurons. It is characterised by insulin-dependent diabetes mellitus, optic nerve atrophy, diabetes insipidus, hearing loss and neurodegeneration. Wolfram syndrome is a rare autosomal recessive disorder caused by pathogenic variants in the WFS1 gene.
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