Regenerative Medicine Program, and Department of Biochemistry and Medical Genetics, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada.
Division of Medical Genetics, Department of Paediatrics, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada.
Neuropathol Appl Neurobiol. 2020 Dec;46(7):735-750. doi: 10.1111/nan.12619. Epub 2020 Apr 20.
Rett Syndrome (RTT) is a neurodevelopmental disorder caused by Methyl CpG Binding Protein 2 (MECP2) gene mutations. Previous studies of MeCP2 in the human brain showed variable and inconsistent mosaic-pattern immunolabelling, which has been interpreted as a reflection of activation-state variability. We aimed to study post mortem MeCP2 and BDNF (MeCP2 target) degradation and brain region-specific detection in relation to RTT pathophysiology.
We investigated MeCP2 and BDNF stabilities in non-RTT human brains by immunohistochemical labelling and compared them in three brain regions of RTT and controls.
In surgically excised samples of human hippocampus and cerebellum, MeCP2 was universally detected. There was no significantly obvious difference between males and females. However, post mortem delay in autopsy samples had substantial influence on MeCP2 detection. Immunohistochemistry studies in RTT patients showed lower MeCP2 detection in glial cells of the white matter. Glial fibrillary acidic protein (GFAP) expression was also reduced in RTT brain samples without obvious change in myelin basic protein (MBP). Neurons did not show any noticeable decrease in MeCP2 detection. BDNF immunohistochemical detection showed an astroglial/endothelial pattern without noticeable difference between RTT and controls.
Our findings indicate that MeCP2 protein is widely expressed in mature human brain cells at all ages. However, our data points towards a possible white matter abnormality in RTT and highlights the importance of studying human RTT brain tissues in parallel with research on animal and cell models of RTT.
雷特综合征（RTT）是一种由甲基化 CpG 结合蛋白 2（MECP2）基因突变引起的神经发育障碍。之前对人类大脑中 MeCP2 的研究显示，免疫标记存在不同且不一致的镶嵌模式，这被解释为激活状态变异性的反映。我们旨在研究与 RTT 病理生理学相关的死后 MeCP2 和脑源性神经营养因子（MeCP2 靶标）降解以及大脑区域特异性检测。
我们通过免疫组织化学标记研究了非 RTT 人类大脑中的 MeCP2 稳定性，并比较了 RTT 和对照组三个大脑区域的稳定性。
在手术切除的人类海马体和小脑样本中，普遍检测到 MeCP2。男性和女性之间没有明显的显著差异。然而，尸检样本的死后延迟对 MeCP2 的检测有实质性的影响。在 RTT 患者的免疫组织化学研究中，发现白质胶质细胞中的 MeCP2 检测水平较低。RTT 脑样本中的神经胶质纤维酸性蛋白（GFAP）表达也减少，而髓鞘碱性蛋白（MBP）没有明显变化。神经元中没有明显的 MeCP2 检测减少。BDNF 免疫组织化学检测显示出一种星形胶质细胞/内皮细胞模式，在 RTT 和对照组之间没有明显差异。
我们的研究结果表明，MeCP2 蛋白在所有年龄段的成熟人类脑细胞中广泛表达。然而，我们的数据表明 RTT 中可能存在白质异常，并强调了在 RTT 动物和细胞模型研究的同时研究人类 RTT 脑组织的重要性。
