Hyperphosphorylated tau aggregates in the cortex and hippocampus of transgenic mice with mutant human FTDP-17 Tau and lacking the PARK2 gene
Hyperphosphorylated tau aggregates in the cortex and hippocampus of transgenic mice with mutant human FTDP-17 Tau and lacking the PARK2 gene
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DOI：
10.1007/s00401-008-0470-3
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发表时间：
2009-02-01
影响因子：
12.7
通讯作者：
Sanchez, Marina P.
中科院分区：
文献类型：
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作者：
Guerrero, Rosa;Navarro, Paloma;Sanchez, Marina P.
编码parkin的PARK 2基因的突变引起常染色体隐性青少年帕金森综合征，但也在诊断为某些tau蛋白病的患者中发现。相反，编码tau蛋白的MAPT基因突变存在于某些类型的帕金森综合征中。为了研究这两种蛋白质之间的可能关系，我们产生了一种双突变小鼠，其缺乏PARK 2并且过表达hTauVLW转基因，这是FTDP-17中存在的tau蛋白的突变形式。PARK 2的独立缺失或hTauVLW转基因的过表达产生轻微的表型改变，而在hTauVLW转基因小鼠中观察到parkin表达的显著增加。然而，双突变小鼠存在记忆和探索缺陷，以及PHF-1和AT 8过度磷酸化tau表位在神经元中的积累。这些现象与反应性星形胶质细胞增多症、DNA片段化和可变的脑萎缩相结合。在这里，我们表明，皮质和海马神经元的双突变小鼠发展嗜银Gallyas-Braak聚集的磷酸化tau从3个月大。它们的数量在老年动物中减少。此外，许多磷酸化的tau聚集体与构象依赖性的Alz-50抗体和S-硫磺素染色鉴定。当在过表达hTauVLW转基因的小鼠中删除parkin时，脊髓的小脑运动核也呈现Alz-50、AT 8和PHF 1过度磷酸化的tau聚集体，这在早期开始。因此，小鼠中PARK 2基因缺失与hTauVLW过表达的组合产生异常过度磷酸化的tau聚集体，类似于在诊断患有某些tau蛋白病的患者的脑中观察到的那些。鉴于这些变化，这些小鼠可能有助于理解这些疾病的分子过程，它们可能有助于开发新的治疗策略来治疗与tau和parkin蛋白相关的神经退行性疾病。
Mutations in the PARK2 gene encoding parkin cause autosomal recessive juvenile parkinsonism, but have also been found in patients diagnosed with certain tauopathies. Conversely, mutations in the MAPT gene encoding tau are present in some types of parkinsonism. In order to investigate the possible relationship between these two proteins, we generated a double mutant mouse that is deficient in PARK2 and that over-expresses the hTauVLW transgene, a mutant form of the tau protein present in FTDP-17. Independent deletion of PARK2 or over-expression of the hTauVLW transgene produces mild phenotypic alterations, while a substantial increase in parkin expression is observed in hTauVLW transgenic mice. However, double mutant mice present memory and exploratory deficits, and accumulation of PHF-1 and AT8 hyperphosphorylated tau epitopes in neurons. These phenomena are coupled with reactive astrocytosis, DNA fragmentation, and variable cerebral atrophy. Here, we show that cortical and hippocampal neurons of double mutant mice develop argyrophilic Gallyas-Braak aggregates of phosphorylated tau from 3 months of age. Their number decreases in old animals. Moreover, numerous phosphorylated tau aggregates were identified with the conformation-dependent Alz-50 antibody and the S-Thioflavin staining. Ventral motor nuclei of the spinal cord also present Alz-50, AT8, and PHF1 hyperphosphorylated tau aggregates when parkin is deleted in mice over-expressing the hTauVLW transgene, begining at early ages. Thus, the combination of PARK2 gene deletion with hTauVLW over-expression in mice produces abnormal hyperphosphorylated tau aggregates, similar to those observed in the brain of patients diagnosed with certain tauopathies. In the light of these changes, these mice may help to understand the molecular processes responsible for these diseases, and they may aid the development of new therapeutic strategies to treat neurodegenerative diseases related to tau and parkin proteins.