Transcriptional Assessment of Striatal mRNAs as Valid Biomarkers of Disease Progression in Three Mouse Models of Huntington's Disease
Transcriptional Assessment of Striatal mRNAs as Valid Biomarkers of Disease Progression in Three Mouse Models of Huntington's Disease
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DOI：
10.3233/jhd-190389
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发表时间：
2020-01-01
影响因子：
3.1
通讯作者：
Park, Larry C.
中科院分区：
文献类型：
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作者：
Ghavami, Afshin;Olsen, Michael;Park, Larry C.
背景：亨廷顿病 (HD) 是一种进行性神经退行性疾病，主要影响基底神经节，导致情感、认知、行为和运动能力下降。 HD 中神经元丢失的主要部位是基底神经节的纹状体部分，晚期 HD 中 GABA 能中型多棘神经元 (MSN) 几乎完全丢失。 目的：基于突变亨廷顿 (mHTT) 蛋白通过转录失调损伤神经元的假设，我们着手在特征明确的转基因小鼠模型 R6/2 和两个敲入模型 (KI) 中建立 HD 疾病进展的转录谱； zQ175KI（表达突变型小鼠/人嵌合Htt蛋白）和HdhQ200 HET KI（携带扩展的小鼠CAG重复序列的一个等位基因）。方法：在本研究中，我们使用定量PCR（qPCR）来评估神经传递、神经炎症和能量代谢标志物的纹状体mRNA水平。结果：在分析和比较症状前和症状阶段的转录本后，在基底细胞中表达的标志物神经节 MSN 通常参与维持正常的神经传递，显示出基因型特异性的 mRNA 表达下降，其模式与人类研究一致。相比之下，在这些 HD 动物模型中，与神经炎症和能量代谢相关的转录本大多不受影响。结论：我们的结果表明，与神经传递相关的转录本显着减少，并且与 zQ175KI 和 R6/2 转基因小鼠模型中的疾病进展一致。
Background: Huntington's disease (HD) is a progressive neurodegenerative disorder that prominently affects the basal ganglia, leading to affective, cognitive, behavioral, and motor decline. The primary site of neuron loss in HD is the striatal part of the basal ganglia, with GABAergic medium size spiny neurons (MSNs) being nearly completely lost in advanced HD.Objective: Based on the hypothesis that mutant huntingtin (mHTT) protein injures neurons via transcriptional dysregulation, we set out to establish a transcriptional profile of HD disease progression in the well characterized transgenic mouse model, R6/2, and two Knock-in models (KI); zQ175KI (expressing mutant mouse/human chimeric Htt protein) and HdhQ200 HET KI (carrying one allele of expanded mouse CAG repeats).Methods: In this study, we used quantitative PCR (qPCR) to evaluate striatal mRNA levels of markers of neurotransmission, neuroinflammation, and energy metabolism.Results: After analyzing and comparing transcripts from pre-symptomatic and symptomatic stages, markers expressed in the basal ganglia MSNs, which are typically involved in maintaining normal neurotransmission, showed a genotype-specific decrease in mRNA expression in a pattern consistent with human studies. In contrast, transcripts associated with neuroinflammation and energy metabolism were mostly unaffected in these animal models of HD.Conclusion: Our results show that transcripts linked to neurotransmission are significantly reduced and are consistent with disease progression in both zQ175KI and R6/2 transgenic mouse models.