Effects of CAG repeat length, HTT protein length and protein context on cerebral metabolism measured using magnetic resonance spectroscopy in transgenic mouse models of Huntington's disease
Effects of CAG repeat length, HTT protein length and protein context on cerebral metabolism measured using magnetic resonance spectroscopy in transgenic mouse models of Huntington's disease
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DOI：
10.1111/j.1471-4159.2005.03411.x
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发表时间：
2005-10-01
影响因子：
4.7
通讯作者：
Beal, MF
中科院分区：
文献类型：
--
作者：
Jenkins, BG;Andreassen, OA;Beal, MF
亨廷顿氏病是一种神经退行性疾病，由亨廷顿蛋白N-末端CAG重复序列扩增引起。我们在五种不同的小鼠模型中使用体内磁共振波谱检查了脑代谢物水平的纵向变化。在具有150个CAG重复的小鼠（R6/2品系）中，纹状体和皮质中的N-乙酰天冬氨酸（NAA）随时间呈指数下降（> 50%）。在具有82个CAG重复的N171- 82 Q小鼠中，仅限于纹状体的线性降低。NAA的指数和线性下降都被组织学测量的神经元面积的减少所抵消。具有72个CAG重复但低表达水平的酵母人工染色体转基因小鼠的纹状体NAA损失比N171- 82 Q小鼠少（15%对43%）。我们评估了次黄嘌呤磷酸核糖转移酶基因（HPRT）上约146个CAG重复的小鼠中基因背景的影响。与R6/2和N171- 82 Q小鼠中的体重减轻相反，HPRT小鼠形成肥胖表型。这些小鼠表现出小的纹状体NAA损失（21%），以及磁共振（MR）光谱可检测到的脑脂质可能增加和脑水T1降低。我们的研究结果表明，深刻的代谢缺陷，受到CAG重复序列长度，以及基因表达水平和蛋白质背景的强烈影响。
Huntington's disease is a neurodegenerative illness caused by expansion of CAG repeats at the N-terminal end of the protein huntingtin. We examined longitudinal changes in brain metabolite levels using in vivo magnetic resonance spectroscopy in five different mouse models. There was a large (> 50%) exponential decrease in N-acetyl aspartate (NAA) with time in both striatum and cortex in mice with 150 CAG repeats (R6/2 strain). There was a linear decrease restricted to striatum in N171-82Q mice with 82 CAG repeats. Both the exponential and linear decreases of NAA were paralleled in time by decreases in neuronal area measured histologically. Yeast artificial chromosome transgenic mice with 72 CAG repeats, but low expression levels, had less striatal NAA loss than the N171-82Q mice (15% vs. 43%). We evaluated the effect of gene context in mice with an approximate 146 CAG repeat on the hypoxanthine phosphoribosyltransferase gene (HPRT). HPRT mice developed an obese phenotype in contrast to weight loss in the R6/2 and N171-82Q mice. These mice showed a small striatal NAA loss (21%), and a possible increase in brain lipids detectable by magnetic resonance (MR) spectroscopy and decreased brain water T1. Our results indicate profound metabolic defects that are strongly affected by CAG repeat length, as well as gene expression levels and protein context.