Mockenhaupt Karli, Zarei-Kheirabadi Masoumeh, Gonsiewski Alexandra K, Hariprashad Avani, Dain Lauren, Verheijen Johannes, Singh Sandeep K, Kordula Tomasz
Department of Cellular, Molecular, and Genetic Medicine, School of Medicine and the Massey Comprehensive Cancer Center, Virginia Commonwealth University, Richmond, Virginia, USA.
FASEB J. 2025 Jul 31;39(14):e70824. doi: 10.1096/fj.202501225RR.
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.
虽然持续性神经炎症和神经退行性变是许多疾病的标志，但引发神经退行性变的确切机制尚未完全明确。神经退行性变伴随着星形胶质细胞的激活，星形胶质细胞具有神经保护和神经毒性两种功能。关于星形胶质细胞的内在功能障碍如何导致神经炎症和神经退行性变，人们了解得更少。为了研究星形胶质细胞驱动的神经退行性变，我们检查了成年星形胶质细胞特异性阴阳1（Yy1）条件性敲除小鼠的衰老小脑，这些小鼠含有成熟不当的功能失调星形胶质细胞。我们发现，发育过程中从星形胶质细胞中删除Yy1会导致成年小鼠随后出现小脑神经退行性变。神经退行性变伴随着星形胶质细胞形态和星形胶质细胞特异性基因表达的深刻变化，以及在小脑神经退行性变和浦肯野细胞（PC）丢失之前出现的严重神经炎症。从机制上讲我们发现，伯格曼胶质细胞（BG）持续表达β-连环蛋白与其腺瘤性息肉病结肠（APC）表达降低以及谷氨酸能神经元突触蛋白表达减少相关，这表明Yy1支持β-连环蛋白降解和适当的BG形态所需的星形胶质细胞APC表达。我们的研究结果突出了YY1在维持小脑星形胶质细胞功能中的关键作用，并表明星形胶质细胞功能障碍对小脑完整性、功能有广泛影响，并导致神经退行性变。
