Niu Li, Ye Cuifang, Sun Yun, Peng Ting, Yang Shiming, Wang Weixi, Li He
1Department of Histology and Embryology, School of Basic Medical Sciences, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan, 430030 People's Republic of China.
2Institute for Brain Sciences, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030 People's Republic of China.
Cell Biosci. 2018 Jul 4;8:41. doi: 10.1186/s13578-018-0239-x. eCollection 2018.
Iron accumulation in basal ganglia accompanies neuronal loss in Huntington's disease (HD) patients and mouse disease models. Disruption of HD brain iron homeostasis occurs before the onset of clinical signs. Therefore, investigating the mechanism of iron accumulation is essential to understanding its role in disease pathogenesis.
N171-82Q HD transgenic mice brain iron was detected by using Diaminobenzidine-enhanced Perls' stain. Iron homeostatic proteins including iron response protein 1 (IRP1), transferrin (Tf), ferritin and transferrin receptor (TfR) were determined by using western blotting and immunohistochemistry, and their relative expression levels of RNA were measured by RT-PCR in both N171-82Q HD transgenic mice and HEK293 cells expressing N-terminal of huntingtin.
Iron was increased in striatum and cortex of N171-82Q HD transgenic mice. Analysis of iron homeostatic proteins revealed increased expression of IRP1, Tf, ferritin and TfR in N171-82Q mice striatum and cortex. The same results were obtained in HEK293 cells expressing N-terminal of mutant huntingtin containing 160 CAG repeats.
We conclude that mutant huntingtin may cause abnormal iron homeostatic pathways by increasing IRP1 expression in Huntington's disease, suggesting potential therapeutic target.
在亨廷顿舞蹈症（HD）患者及小鼠疾病模型中，基底神经节中的铁蓄积伴随着神经元丢失。HD脑铁稳态的破坏发生在临床症状出现之前。因此，研究铁蓄积的机制对于理解其在疾病发病机制中的作用至关重要。
使用二氨基联苯胺增强的普鲁士蓝染色检测N171 - 82Q HD转基因小鼠脑铁。通过蛋白质免疫印迹法和免疫组织化学法测定包括铁反应蛋白1（IRP1）、转铁蛋白（Tf）、铁蛋白和转铁蛋白受体（TfR）在内的铁稳态蛋白，并通过RT - PCR在N171 - 82Q HD转基因小鼠和表达亨廷顿蛋白N端的HEK293细胞中测量它们的RNA相对表达水平。
N171 - 82Q HD转基因小鼠的纹状体和皮质中铁含量增加。对铁稳态蛋白的分析显示，N171 - 82Q小鼠纹状体和皮质中IRP1、Tf、铁蛋白和TfR的表达增加。在表达含有160个CAG重复序列的突变亨廷顿蛋白N端的HEK293细胞中也得到了相同的结果。
我们得出结论，在亨廷顿舞蹈症中，突变的亨廷顿蛋白可能通过增加IRP1的表达导致铁稳态途径异常，提示了潜在的治疗靶点。
