Oigodendrocytes in Wolfram syndrome: bystanders or partners in crime?

Wolfram syndrome is a rare hereditary disease, causing diabetes, blindness, deafness and other neurological problems in infants and young adults, and results in death around the age of 30 years. Wolfram patients carry recessive mutations in the WFS1 gene, resulting in loss of function of the WFS1 protein. Loss of WFS1 has been shown to result in ER stress, dysregulated Ca2+ homeostasis and mitochondrial dysfunction. Remarkably, in the brains of Wolfram patients, distinct white matter loss has been observed. Combining this with the observation that myelinating oligodendrocytes are especially sensitive to ER stress, we hypothesize that oligodendrocytes play an important role in the neurodegeneration seen in Wolfram patients. Therefore, in this project, we will investigate what the effect of these ‘diseased’ oligodendrocytes is on the function of ‘healthy’ neurons, focusing on ER stress, mitochondria and cell metabolism as potential underlying mechanisms. In addition, we will further unravel the function of the WFS1 protein by identifying its binding partners in this cellular model system. Finally, we will study the interplay between oligodendrocyte/myelin loss and neurodegeneration in a Wfs1 mouse model, and provide seeding evidence that interfering with the studied cellular processes and WFS1 binding partners can rescue the disease phenotype.Wolfram syndrome is a rare hereditary disease, causing diabetes, blindness, deafness and other neurological problems in infants and young adults, and results in death around the age of 30 years. Wolfram patients carry recessive mutations in the WFS1 gene, resulting in loss of function of the WFS1 protein. Loss of WFS1 has been shown to result in ER stress, dysregulated Ca2+ homeostasis and mitochondrial dysfunction. Remarkably, in the brains of Wolfram patients, distinct white matter loss has been observed. Combining this with the observation that myelinating oligodendrocytes are especially sensitive to ER stress, we hypothesize that oligodendrocytes play an important role in the neurodegeneration seen in Wolfram patients. Therefore, in this project, we will investigate what the effect of these ‘diseased’ oligodendrocytes is on the function of ‘healthy’ neurons, focusing on ER stress, mitochondria and cell metabolism as potential underlying mechanisms. In addition, we will further unravel the function of the WFS1 protein by identifying its binding partners in this cellular model system. Finally, we will study the interplay between oligodendrocyte/myelin loss and neurodegeneration in a Wfs1 mouse model, and provide seeding evidence that interfering with the studied cellular processes and WFS1 binding partners can rescue the disease phenotype.