Morigaki Ryoma, Yoshida Tomoko, Fujikawa Joji, Crittenden Jill R, Graybiel Ann M
McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Int J Mol Sci. 2025 Sep 3;26(17):8573. doi: 10.3390/ijms26178573.
The pathogenesis and pathophysiology of Huntington's disease (HD) are still incompletely understood, despite the remarkable advances in identifying the molecular effects of the mutation in this disease. Clinical positron emission tomography studies suggest that phosphodiesterase 10A (PDE10A) declines earlier than dopamine D1 and D2 receptors in HD, indicating that it might serve as a key molecular marker in understanding disease mechanisms. In movement disorders, mutations in the genes encoding PDE10A and G-protein α subunit (Gα), both critical cAMP regulators in striatal spiny projection neurons, have been linked to chorea and dystonia. These observations highlight the potential importance of striatal cyclic AMP (cAMP) signaling in these disorders, but how such dysfunction could come is unknown. Here, we suggest that a key to understanding signaling dysfunction might be to evaluate these messenger systems in light of the circuit-level compartmental organization of the caudoputamen, in which there is particular vulnerability of the striosome compartment in HD. We developed machine learning algorithms to define with high precision and reproducibility the borders of striosomes in the brains of Q175 knock-in (Q175KI) HD mice from 3-12 months of age. We demonstrate that the expression of multiple molecules, including Gα, PDE10A, dopamine D1 and D2 receptors, and adenosine A2A receptors, is significantly reduced in the striosomes of Q175KI mice as compared to wildtype controls, across 3, 6, and 12 months of age. By contrast, mu-opioid receptor (MOR1) expression is uniquely upregulated, suggesting a compartment-specific and age-dependent shift in molecular profiles in the Q175KI HD mouse model caudoputamen. These differential changes may serve as a useful platform to determine factors underlying the greater vulnerability of striatal projection neurons in the striosomes than in the matrix in HD.
尽管在确定亨廷顿舞蹈症（HD）突变的分子效应方面取得了显著进展，但其发病机制和病理生理学仍未完全明确。临床正电子发射断层扫描研究表明，在HD中，磷酸二酯酶10A（PDE10A）的下降早于多巴胺D1和D2受体，这表明它可能是理解疾病机制的关键分子标志物。在运动障碍中，编码PDE10A和G蛋白α亚基（Gα）的基因突变与舞蹈症和肌张力障碍有关，这两种基因都是纹状体棘状投射神经元中关键的环磷酸腺苷（cAMP）调节因子。这些观察结果凸显了纹状体cAMP信号在这些疾病中的潜在重要性，但这种功能障碍是如何产生的尚不清楚。在这里，我们认为理解信号功能障碍的一个关键可能是根据尾壳核的回路水平分区组织来评估这些信使系统，在HD中，纹状体小体分区特别脆弱。我们开发了机器学习算法，以高精度和可重复性定义3至12月龄Q175基因敲入（Q175KI）HD小鼠大脑中纹状体小体的边界。我们证明，与野生型对照相比，在3、6和12月龄的Q175KI小鼠的纹状体小体中，包括Gα、PDE10A、多巴胺D1和D2受体以及腺苷A2A受体在内的多种分子的表达显著降低。相比之下，μ-阿片受体（MOR1）的表达独特地上调，这表明在Q175KI HD小鼠模型的尾壳核中，分子谱存在分区特异性和年龄依赖性的变化。这些差异变化可能是一个有用平台，有助于确定HD中纹状体小体中纹状体投射神经元比基质中更易受损的潜在因素。
