Shukkur Ebrahim Abdul, Shimohata Atsushi, Akagi Takumi, Yu Wenxin, Yamaguchi Mika, Murayama Miyuki, Chui Dehua, Takeuchi Tamaki, Amano Kenji, Subramhanya Karthik Harve, Hashikawa Tsutomu, Sago Haruhiko, Epstein Charles J, Takashima Akihiko, Yamakawa Kazuhiro
Laboratory for Neurogenetics, RIKEN Brain Science Institute, Saitama, Japan.
Hum Mol Genet. 2006 Sep 15;15(18):2752-62. doi: 10.1093/hmg/ddl211. Epub 2006 Aug 4.
Trisomy 21 or Down syndrome (DS) is the most common genetic birth defect associated with mental retardation. The over-expression of genes on chromosome 21, including SOD1 (Cu/Zn superoxide dismutase) and APP (amyloid-beta precursor protein) is believed to underlie the increased oxidative stress and neurodegeneration commonly described in DS. However, a segmental trisomy 16 mouse model for DS, Ts1Cje, has a subset of triplicated human chromosome 21 gene orthologs that exclude APP and SOD1. Here, we report that Ts1Cje brain shows decreases of mitochondrial membrane potential and ATP production, increases of reactive oxygen species, hyperphosphorylation of tau without NFT formation, increase of GSK3beta and JNK/SAPK activities and unaltered AbetaPP metabolism. Our findings suggest that genes on the trisomic Ts1Cje segment other than APP and SOD1 can cause oxidative stress, mitochondrial dysfunction and hyperphosphorylation of tau, all of which may play critical roles in the pathogenesis of mental retardation in DS.
21三体综合征或唐氏综合征（DS）是与智力发育迟缓相关的最常见的遗传性出生缺陷。21号染色体上基因的过度表达，包括超氧化物歧化酶1（Cu/Zn超氧化物歧化酶）和淀粉样前体蛋白（APP），被认为是DS中常见的氧化应激增加和神经退行性变的基础。然而，一种用于DS的16号染色体节段三体小鼠模型Ts1Cje，有一部分重复的人类21号染色体基因直系同源物，其中不包括APP和超氧化物歧化酶1。在此，我们报告Ts1Cje小鼠脑显示线粒体膜电位和ATP生成减少、活性氧增加、tau蛋白过度磷酸化但无神经原纤维缠结形成、糖原合成酶激酶3β（GSK3β）和应激活化蛋白激酶（JNK/SAPK）活性增加以及淀粉样前体蛋白（AβPP）代谢未改变。我们的研究结果表明，除APP和超氧化物歧化酶1外，三体Ts1Cje节段上的基因可导致氧化应激、线粒体功能障碍和tau蛋白过度磷酸化，所有这些可能在DS智力发育迟缓的发病机制中起关键作用。
