Defective Astrocyte Maturation Drives Cerebellar Neuroinflammation and Degeneration

While persistent neuroinflammation and neurodegeneration are hallmarks of many diseases, the exact mechanisms triggering neurodegeneration are not fully established. Neurodegeneration is accompanied by activation of astrocytes that can have both neuroprotective and neurotoxic functions. Much less is known about how intrinsic dysfunction of astrocytes can lead to neuroinflammation and neurodegeneration. To study astrocyte-driven neurodegeneration, we examined aging cerebella of adult astrocyte-specific Yin Yang1 (Yy1) conditional knockout mice that contain improperly matured dysfunctional astrocytes. We found that deletion of Yy1 from astrocytes during development results in subsequent cerebellar neurodegeneration in adult mice. The neurodegeneration was accompanied by profound changes in astrocyte morphologies and expression of astrocyte-specific genes, and development of severe neuroinflammation that preceded cerebellar neurodegeneration and Purkinje cell (PC) loss. Mechanistically, we found that sustained β-catenin expression by Bergmann glia (BG) correlated with their decreased adenomatous polyposis coli (APC) expression and diminished expression of synaptic proteins by glutamatergic neurons, suggesting that Yy1 supports astrocytic APC expression needed for β-catenin degradation and proper BG morphology. Our findings highlight the critical role of YY1 in sustaining cerebellar astrocyte functions and suggest that dysfunction of astrocytes has widespread consequences for cerebellar integrity, function, and leads to neurodegeneration.