Tallaksen-Greene Sara J, Ordway Jared M, Crouse Andrew B, Jackson Walker S, Detloff Peter J, Albin Roger L
Department of Neurology, University of Michigan, Ann Arbor, Michigan 48109-0585, USA.
J Comp Neurol. 2003 Oct 13;465(2):205-19. doi: 10.1002/cne.10855.
We reported previously a model of polyglutamine repeat disorders with insertion of 146 CAG repeats into the murine hypoxanthine phosphoribosyl transferase locus (Hprt(CAG)146; Ordway et al. [1997] Cell 91:753-763), which does not normally contain polyglutamine repeats. These mice develop an adult-onset neurologic phenotype of incoordination, involuntary limb clasping, seizures, and premature death. Histologic analysis demonstrates widespread ubiquinated neuronal intranuclear inclusions (NIIs). We now report characterization of the age of onset of behavioral abnormalities, correlated with the time course of occurrence of NIIs in several brain regions, and the occurrence of NIIs in non-neuronal tissues. Onset of behavioral abnormalities occurred at approximately 22 weeks of age. There was variable time course of expression of NIIs in several brain regions. Assessment of several non-neuronal tissues revealed nuclear inclusions in hepatocytes and choroid plexus epithelium. Gamma-aminobutyric acid (GABA)/benzodiazepine receptors, dopamine D1-like and D2-like receptors, and type 2 vesicular monoamine transporter (VMAT2) binding sites were assayed before and after the onset of behavioral abnormalities. GABA/benzodiazepine receptors were unchanged either before or after the onset of behavioral abnormalities in any region analyzed, whereas striatal D1-like and D2-like receptors were diminished after but not before the onset of symptoms. Dorsal striatal VMAT2 binding sites were decreased before the onset of behavioral changes. Mitochondrial electron transport chain components were assayed with histochemical methods before and after the onset of behavioral changes. There was no change in behaviorally presymptomatic or symptomatic animals. Hprt(CAG)146 mice did not exhibit increased susceptibility to the mitochondrial toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Hprt(CAG)146 mice are a useful model for studying polyglutamine repeat disorders.
我们之前报道过一种多聚谷氨酰胺重复序列疾病模型，该模型是在小鼠次黄嘌呤磷酸核糖基转移酶基因座（Hprt(CAG)146；Ordway等人，[1997]《细胞》91:753 - 763）中插入了146个CAG重复序列，该基因座正常情况下不包含多聚谷氨酰胺重复序列。这些小鼠会出现成年后发病的神经学表型，包括运动不协调、肢体不自主紧握、癫痫发作和过早死亡。组织学分析显示广泛存在泛素化的神经元核内包涵体（NIIs）。我们现在报告行为异常发病年龄的特征，及其与几个脑区NIIs出现的时间进程以及非神经组织中NIIs出现情况的相关性。行为异常大约在22周龄时出现。几个脑区中NIIs的表达时间进程各不相同。对几个非神经组织的评估显示肝细胞和脉络丛上皮细胞中有核内包涵体。在行为异常出现之前和之后，检测了γ-氨基丁酸（GABA）/苯二氮䓬受体、多巴胺D1样和D2样受体以及2型囊泡单胺转运体（VMAT2）结合位点。在分析的任何区域，行为异常出现之前或之后，GABA/苯二氮䓬受体均未发生变化，而纹状体D1样和D2样受体在症状出现后减少，而非在症状出现前减少。行为变化出现之前，背侧纹状体VMAT2结合位点就已减少。在行为变化出现之前和之后，用组织化学方法检测了线粒体电子传递链成分。行为出现症状前或出现症状的动物均未发生变化。Hprt(CAG)146小鼠对线粒体毒素1-甲基-4-苯基-1,2,3,6-四氢吡啶未表现出易感性增加。Hprt(CAG)146小鼠是研究多聚谷氨酰胺重复序列疾病的有用模型。
