8th International Wolfram Symposium Presentation Karan Ahuja, Marjan Vandenabeele, Arefe Nami, Catherine Verfaillie, Lieve Moons, Lies De Groef
8th International Wolfram Symposium Presentation Karan Ahuja1, Marjan Vandenabeele2,3, Arefe Nami1, Catherine Verfaillie1, Lieve Moons2, Lies De Groef3
Oligodendrocytes in Wolfram syndrome: bystanders or partners in crime?
1Development and Regeneration Department, KU Leuven Stem Cell Institute, Leuven, Belgium 2Neural Circuit Development and Regeneration Research Group, Biology Department, KU Leuven Brain Institute, Leuven, Belgium
3Cellular Communication and Neurodegeneration Research Group, Biology Department, KU Leuven Brain Institute, Leuven, Belgium
Abstract: Up till today, the neurodegenerative pathology associated with Wolfram syndrome (WS) is unstoppable. This treatment gap is at least in part due to the limited understanding of the underlying cellular mechanisms. In particular, it is becoming increasingly clear that –although neurons eventually die– there is a central role for glial cell types in most neurodegenerative disorders and it is essential to determine which of these cell types is the catalyst of the disease processes leading to WS, so that future therapies can be targeted to this cell type. In this study, based on recent evidence suggesting that the neurodegenerative component of WS could be driven by an oligodendrocyte rather than a neuronal pathology, we aimed to 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.
Our studies in iPSC-derived oligodendrocytes from WS patients reveal that these may be more vulnerable to ER stress and display signs of mitochondrial dysfunction. This, together with their seemingly reduced capacity to transfer metabolites and thereby support axons, suggests that oligodendrocyte dysfunction may, at least partially, be underlying the neurodegenerative component of WS. Next, we validated these findings in vivo, by investigating the retina and optic nerve of the Wfs1 KO mouse. We found that functional and glial cell alterations precede structural neuronal changes, and that these animals have problems with the oligodendrocyte cell lineage, leading to a decreased oligodendrocyte precursor cell number, a thinner myelin sheet and more signs of axonal degeneration in the Wfs1 KO animals. Finally, MRI studies of the brain of these Wfs1 KO mice showed a reduction in the volume of several brain regions, including the cerebellum, brainstem and corpus callosum which are also affected in WS patients– as well as changes in the apparent diffusion coefficient, pointing towards neurodegeneration and changes in myelination. Based on these data, it is tempting to speculate that the white matter changes and neuronal loss observed in WS patients is at least partly caused by problems with the supportive functions of oligodendrocytes: signal transduction via myelination and metabolic support of axons. This suggests that future WS therapies may need to target oligodendrocytes, rather than or in addition to neurons. All in all, our findings indicate that the eye is a window to the brain, with the retina reflecting the pathological processes ongoing in the brain.
Points noted:
• Wfs1 KO mice
• Also shared preliminary in vitro data where ER stress, mitochondrial dysfunction and cell death were observed in WS patient derived cell lines.