Abstract
Purpose :
Wolfram syndrome (WS) is a rare childhood disease characterized by diabetes mellitus, diabetes insipidus, blindness, deafness, neurodegeneration and eventually early death, due to autosomal recessive mutations in the WFS1 (and WFS2) gene. While it is categorized as a neurodegenerative disease and, by definition, is characterized by the loss of neurons in the CNS, expression studies and MRI studies in patients and WS rodent models suggest a role for the oligodendroglia. In this study, we sought to determine whether oligodendroglia are indeed affected in WS and whether their dysfunction may be the primary cause of the disease, leading to secondary neurodegeneration due to a loss of their supportive functions.
Methods :
Wfs1△exon8 mice underwent a battery of in vivo tests to study retinal function and integrity, as well as post mortem histological analyses of the retina and optic nerve, and biochemical assays to assess WS disease processes. WS patient iPSC-derived oligodendroglia and isogenic controls were studied by transcriptomics, lipidomics and cellular assays of ER and mitochondrial function.
Results :
We show that 7.5-month-old Wfs1△exon8 mice display signs of abnormal myelination and a reduced number of oligodendrocyte precursor cells (OPCs) as well as abnormal axonal conduction in the optic nerve. An MRI study of the brain furthermore reveals grey and white matter loss in the cerebellum, brainstem, and superior colliculus, as is seen in WS patients. A deep phenotyping study of WS patient iPSC-derived OPCs/pre-myelinating oligodendrocytes reveals normal differentiation, mitochondria-associated endoplasmic reticulum (ER) membrane interactions and mitochondrial function, and no overt signs of ER stress. However, transcriptional changes at the OPC-neuron synapse suggest that the neuronal activity-dependent regulation of OPC cellular behavior may be disturbed, which may have major implications for neuronal health.
Conclusions :
While no clear evidence of large abnormalities in the intrinsic cellular function of oligodendrocytes was found, we do reveal evidence to suggest a defect in the synaptic contacts of the OPCs with neurons. Follow-up studies are thus needed to further elucidate which cell types and cellular compartments should be targeted by future neuroprotective or -restorative treatments for WS.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.