Huntington’s disease (HD) is caused by an expansion of CAG triplets in the huntingtin gene, leading to severe neuropathological changes that result in a devasting and lethal phenotype. Neurodegeneration in HD begins in the striatum and spreads to other brain regions such as cortex and hippocampus, causing motor and cognitive dysfunctions. To understand the signaling pathways involved in HD, animal models that mimic the human pathology are used. The R6/2 mouse as model of HD was already shown to present major neuropathological changes in the caudate putamen and other brain regions, but recently established biomarkers in HD patients were yet not analyzed in these mice. We therefore performed an in-depth analysis of R6/2 mice to establish new and highly translational readouts focusing on Ctip2 as biological marker for motor system-related neurons and translocator protein (TSPO) as a promising readout for early neuroinflammation. Our results validate already shown pathologies like mutant huntingtin aggregates, ubiquitination, and brain atrophy, but also provide evidence for decreased tyrosine hydroxylase and Ctip2 levels as indicators of a disturbed motor system, while vesicular acetyl choline transporter levels as marker for the cholinergic system barely change. Additionally, increased astrocytosis and activated microglia were observed by GFAP, Iba1 and TSPO labeling, illustrating, that TSPO is a more sensitive marker for early neuroinflammation compared to GFAP and Iba1. Our results thus demonstrate a high sensitivity and translational value of Ctip2 and TSPO as new marker for the preclinical evaluation of new compounds in the R6/2 mouse model of HD.

亨廷顿舞蹈病（HD）是由亨廷顿基因中的CAG三联体扩增引起的，导致严重的神经病理学改变，导致毁灭性和致命的表型。HD的神经变性始于纹状体，并扩散到其他大脑区域，例如皮层和海马，导致运动和认知功能障碍。为了理解高清所涉及的信号传导途径，使用了模仿人类病理的动物模型。作为HD模型的R6 / 2小鼠已经显示出在尾状壳核和其他脑区域中存在主要的神经病理学改变，但是最近尚未在这些小鼠中分析HD患者中建立的生物标志物。因此，我们对R6 / 2小鼠进行了深入分析，以建立新的高度翻译的读数，重点是Ctip2作为运动系统相关神经元的生物标记，而移位蛋白（TSPO）作为早期神经炎症的有希望的读数。我们的结果验证了已经显示出的突变性亨廷顿蛋白聚集体，泛素化和脑萎缩等病理，但也提供了酪氨酸羟化酶和Ctip2水平降低作为运动系统障碍的指标的证据，而水泡乙酰胆碱转运蛋白水平却是胆碱能系统的标志。此外，通过GFAP，Iba1和TSPO标记观察到星形胶质细胞增多和活化的小胶质细胞增加，这说明与GFAP和Iba1相比，TSPO是早期神经炎症的更敏感标志。