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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Dysregulation of dopamine receptor D2 as a sensitive measure for Huntington disease pathology in model mice
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Dysregulation of dopamine receptor D2 as a sensitive measure for Huntington disease pathology in model mice

机译：多巴胺受体D2失调是模型小鼠亨廷顿病病理的敏感指标

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The ability to quantitatively evaluate the impact of a potential therapeutic intervention for Huntington disease (HD) in animal models for the disease is a critical step in the pathway to development of an effective therapy for this devastating neuro-degenerative disorder. We report here an approach that combines a cell-based assay's quantitative accuracy and direct relationship to molecular processes with the ability to directly monitor effects in HD model mouse neurons. To accomplish this goal, we have developed an accurate quantitative reporter assay for a transcript known to be down-regulated as an early consequence of mutant huntingtin expression. This system uses mouse strains carrying a GFP reporter for the expression of the dopamine receptor D2, expressed in the medium spiny neurons of the basal ganglion. This receptor consistently demonstrates reduced expression in patients and murine models, and the FACS-based assay gives a highly accurate and quantitative readout of this pathology in mouse neurons expressing mutant huntingtin. For four genetic models and one viral model, a highly reproducible time course of loss of reporter expression is observed. This quantitative measure of HD pathology can be used to measure the effects of HD therapeutics in small cohorts with high confidence. We further demonstrate that the introduction of an shRNA against the huntingtin trans-gene by virus can improve this pathological status in medium spiny neurons transduced with the construct. We believe this system can be of great utility in the validation of effective therapeutic interventions for HD.
机译：在该疾病的动物模型中，定量评估亨廷顿病（HD）潜在治疗干预措施的影响的能力是开发针对这种破坏性神经退行性疾病的有效疗法的关键步骤。我们在这里报告了一种方法，该方法结合了基于细胞的测定的定量准确性以及与分子过程的直接关系，并具有直接监控HD模型小鼠神经元作用的能力。为了实现这个目标，我们已经开发出一种准确的定量报告基因检测方法，用于检测被突变的亨廷顿蛋白表达的早期结果被下调的转录本。该系统使用携带GFP报告基因的小鼠品系表达多巴胺受体D2，该蛋白在基底神经节的中棘神经元中表达。该受体始终显示出在患者和鼠模型中表达降低，并且基于FACS的测定法在表达突变亨廷顿蛋白的小鼠神经元中高度准确，定量地读出了这种病理。对于四个遗传模型和一个病毒模型，观察到报告子表达丧失的高度可重复的时间过程。 HD病理学的这种定量测量可用于以高置信度来测量HD疗法在小型队列中的作用。我们进一步证明了通过病毒引入针对亨廷顿转基因的shRNA可以改善用构建体转导的中棘神经元的这种病理状态。我们认为该系统在验证HD的有效治疗干预措施方面可以发挥巨大作用。

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