Loss of Hrs in the Central Nervous System Causes Accumulation of Ubiquitinated Proteins and Neurodegeneration
Loss of Hrs in the Central Nervous System Causes Accumulation of Ubiquitinated Proteins and Neurodegeneration
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DOI：
10.2353/ajpath.2008.080684
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发表时间：
2008-12-01
影响因子：
6
通讯作者：
Sugamura, Kazuo
中科院分区：
文献类型：
--
作者：
Tamai, Keiichi;Toyoshima, Masafumi;Sugamura, Kazuo
转运所需的内体分选复合物（ESCRT）蛋白形成多分子复合物，其控制多泡体形成、内体分选并将泛素化膜蛋白（包括细胞表面受体）转运至内体进行降解。越来越多的证据表明，内体功能障碍与体外神经细胞变性有关，但对体内神经疾病与ESCRT蛋白之间的关系知之甚少。在这里，我们专门删除了brs基因，ESCRT-0，在小鼠的神经元交叉loxP侧翼brs小鼠与表达突触蛋白-I Cre蛋白（SynI-cre）的转基因小鼠。组织学分析表明，细胞凋亡和海马CA 3锥体神经元的损失发生在hrs（flox/flox）;SynI-cre小鼠。值得注意的是，hrs（flox/flox）;SynI-cre小鼠积累了泛素化蛋白，如谷氨酸受体和自噬调节蛋白p62。随着年龄的增长，这些分子在海马CA 3神经元和大脑皮层中特别突出。因此，我们发现，在hrs（flox/flox）;SynI-cre小鼠中，运动活性和学习能力都严重降低。这些数据表明，Hrs在体内神经细胞存活中起重要作用，并为已知通常受蛋白质聚集体产生影响的神经退行性疾病提供了动物模型。(Am J Pathol 2008，173：1806-1817; DOI：10.2353/ajpath.2008.080684）
The endosomal sorting complex required for transport (ESCRT) proteins form multimolecular complexes that control multivesicular body formation, endosomal sorting, and transport ubiquitinated membrane proteins (including cell-surface receptors) to the endosomes for degradation. There is accumulating evidence that endosomal dysfunction is linked to neural cell degeneration in vitro, but little is known about the relationship between neural disorders and ESCRT proteins in vivo. Here we specifically deleted the brs gene, ESCRT-0, in the neurons of mice by crossing loxP-flanked brs mice with transgenic mice expressing the synapsin-I Cre protein (SynI-cre). Histological analyses revealed that both apoptosis and a loss of hippocampal CA3 pyramidal neurons occurred in the hrs(flox/flox);SynI-cre mice. Notably, the hrs(flox/flox);SynI-cre mice accumulated ubiquitinated proteins, such as glutamate receptors and an autophagy-regulating protein, p62. These molecules are particularly prominent in the hippocampal CA3 neurons and cerebral cortex with advancing age. Accordingly, we found that both locomotor activity and learning ability were severely reduced in the hrs(flox/flox);SynI-cre mice. These data suggest that Hrs plays an important role in neural cell survival in vivo and provide an animal model for neurodegenerative diseases that are known to be commonly affected by the generation of proteinaceous aggregates. (Am J Pathol 2008, 173:1806-1817; DOI: 10.2353/ajpath.2008.080684)