Dp71 contribution to the molecular scaffold anchoring aquaporine-4 channels in brain macroglial cells
Dp71 contribution to the molecular scaffold anchoring aquaporine-4 channels in brain macroglial cells
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DOI：
10.1002/glia.23941
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发表时间：
2020-11-28
期刊：
影响因子：
6.2
通讯作者：
Vaillend, Cyrille
中科院分区：
文献类型：
--
作者：
Belmaati Cherkaoui, Mehdi;Vacca, Ophelie;Vaillend, Cyrille
Duchenne型肌营养不良症的智力残疾与成人脑中主要的肌营养不良蛋白基因产物Dp 71的丢失有关。Dp 71主要在血管周围的大胶质细胞终足中表达，这表明功能障碍的胶质机制有助于认知障碍。在本研究中，我们研究了Dp 71在小鼠中的选择性损失引起的分子改变，使用半定量免疫金分析在电子显微镜和免疫荧光共聚焦分析在脑切片和纯化的胶质血管单位。在小脑和海马的大胶质细胞毛细血管周围终足中，我们发现水通道蛋白-4（AQP 4）通道的极化分布急剧减少（70%），β-肌营养不良蛋白聚糖减少50%，α 1-突触营养蛋白完全丧失。有趣的是，在海马和皮质，这些影响是不均匀的：AQP 4和AQP 4 ex亚型主要是失去周围的毛细血管，但保存在大血管对应的软脑膜动脉，穿透皮质小动脉，和小动脉的海马裂，表明存在的Dp 71非依赖性池的AQP 4在这些血管结构。总之，Dp 71的耗竭强烈地改变了AQP 4选择性地分布在毛细血管周围的大胶质细胞血管周围的终足。这种效应可能影响水稳态和血脑屏障功能，因此可能导致与Dp 71缺乏相关的突触和认知缺陷。
Intellectual disability in Duchenne muscular dystrophy has been associated with the loss of dystrophin-protein 71, Dp71, the main dystrophin-gene product in the adult brain. Dp71 shows major expression in perivascular macroglial endfeet, suggesting that dysfunctional glial mechanisms contribute to cognitive impairments. In the present study, we investigated the molecular alterations induced by a selective loss of Dp71 in mice, using semi-quantitative immunogold analyses in electron microscopy and immunofluorescence confocal analyses in brain sections and purified gliovascular units. In macroglial pericapillary endfeet of the cerebellum and hippocampus, we found a drastic reduction (70%) of the polarized distribution of aquaporin-4 (AQP4) channels, a 50% reduction of beta-dystroglycan, and a complete loss of alpha 1-syntrophin. Interestingly, in the hippocampus and cortex, these effects were not homogeneous: AQP4 and AQP4ex isoforms were mostly lost around capillaries but preserved in large vessels corresponding to pial arteries, penetrating cortical arterioles, and arterioles of the hippocampal fissure, indicating the presence of Dp71-independent pools of AQP4 in these vascular structures. In conclusion, the depletion of Dp71 strongly alters the distribution of AQP4 selectively in macroglial perivascular endfeet surrounding capillaries. This effect likely affects water homeostasis and blood-brain barrier functions and may thus contribute to the synaptic and cognitive defects associated with Dp71 deficiency.