An inducible oligodendrocyte dysfunction triggered a pathological cascade of massive microglial activation and neurodegeneration.

Abstract

Oligodendrocyte abnormalities disrupt the integrity of myelin and axons, ultimately leading to neuronal loss; however, the pathogenesis of this condition remains unclear, necessitating the development of new animal models. Ddx20 is an RNA-binding factor essential for oligodendrocyte development. To investigate the function of Ddx20 in mature oligodendrocytes, we generated tamoxifen-inducible Ddx20 knockout mice. Systemic deterioration occurred around 4 weeks after tamoxifen administration, characterized by rapid oligodendrocyte loss, massive microglial activation, and subsequent neuronal loss, particularly in the ventral gray matter of the spinal cord. Microglial depletion experiments using PLX3397 administration worsened the phenotype at around 4 weeks, suggesting that microglia play a neuroprotective role up to that point. RNA-seq analysis revealed a significant shift in gene expression after 4 weeks, indicating a change in microglial characteristics at the terminal stage. These results demonstrate that Ddx20 is crucial for maintaining oligodendrocytes, and this novel mouse offers valuable insights how oligodendrocyte abnormalities and subsequent involvement of microglial activation can contribute to neuronal cell death.