Department of Molecular Neurology, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg, Schwabachanlage 6, 91054, Erlangen, Germany.
UK Dementia Research Institute, The University of Edinburgh, Edinburgh, UK.
Acta Neuropathol Commun. 2024 Jan 2;12(1):1. doi: 10.1186/s40478-023-01699-3.
The growing recognition of a dichotomous role of astrocytes in neurodegenerative processes has heightened the need for unraveling distinct astrocytic subtypes in neurological disorders. In multiple system atrophy (MSA), a rare, rapidly progressing atypical Parkinsonian disease characterized by increased astrocyte reactivity. However the specific contribution of astrocyte subtypes to neuropathology remains elusive. Hence, we first set out to profile glial fibrillary acidic protein levels in astrocytes across the human post mortem motor cortex, putamen, and substantia nigra of MSA patients and observed an overall profound astrocytic response. Matching the post mortem human findings, a similar astrocytic phenotype was present in a transgenic MSA mouse model. Notably, MSA mice exhibited a decreased expression of the glutamate transporter 1 and glutamate aspartate transporter in the basal ganglia, but not the motor cortex. We developed an optimized astrocyte isolation protocol based on magnetic-activated cell sorting via ATPase Na+/K+ transporting subunit beta 2 and profiled the transcriptomic landscape of striatal and cortical astrocytes in transgenic MSA mice. The gene expression profile of astrocytes in the motor cortex displayed an anti-inflammatory signature with increased oligodendroglial and pro-myelinogenic expression pattern. In contrast, striatal astrocytes were defined by elevated pro-inflammatory transcripts accompanied by dysregulated genes involved in homeostatic functions for lipid and calcium metabolism. These findings provide new insights into a region-dependent, dichotomous astrocytic response-potentially beneficial in the cortex and harmful in the striatum-in MSA suggesting a differential role of astrocytes in MSA-related neurodegenerative processes.
星形胶质细胞在神经退行性过程中具有双重作用的认识不断提高，这就需要揭示神经紊乱中不同的星形胶质细胞亚型。在多系统萎缩（MSA）中，一种罕见的、迅速进展的非典型帕金森病，其特征是星形胶质细胞反应性增加。然而，星形胶质细胞亚型对神经病理学的具体贡献仍然难以捉摸。因此，我们首先在 MSA 患者的人脑死后运动皮层、壳核和黑质中对星形胶质细胞中的神经胶质纤维酸性蛋白水平进行了分析，观察到了广泛的星形胶质细胞反应。与死后人类研究结果相匹配，在 MSA 转基因小鼠模型中也存在类似的星形胶质细胞表型。值得注意的是，MSA 小鼠在基底神经节中表现出谷氨酸转运体 1 和谷氨酸天冬氨酸转运体表达减少，但在运动皮层中没有。我们开发了一种基于 ATPase Na+/K+ 转运亚基β2 的磁激活细胞分选的优化星形胶质细胞分离方案，并对 MSA 转基因小鼠纹状体和皮质星形胶质细胞的转录组景观进行了分析。运动皮层星形胶质细胞的基因表达谱显示出抗炎特征，少突胶质细胞和促髓鞘生成表达模式增加。相比之下，纹状体星形胶质细胞的特征是促炎转录物升高，并伴有参与脂质和钙代谢稳态功能的失调基因。这些发现为 MSA 中依赖于区域的、二分的星形胶质细胞反应提供了新的见解，这可能对皮层有益，对纹状体有害，表明星形胶质细胞在 MSA 相关神经退行性过程中具有不同的作用。
