Identifying initial triggering events in neurodegenerative disorders is critical to developing preventive therapies. In Huntington’s disease (HD), hyperdopaminergia—probably triggered by the dysfunction of the most affected neurons, indirect pathway spiny projection neurons (iSPNs)—is believed to induce hyperkinesia, an early stage HD symptom. However, how this change arises and contributes to HD pathogenesis is unclear. Here, we demonstrate that genetic disruption of iSPNs function by Ntrk2/Trkb deletion in mice results in increased striatal dopamine and midbrain dopaminergic neurons, preceding hyperkinetic dysfunction. Transcriptomic analysis of iSPNs at the pre-symptomatic stage showed de-regulation of metabolic pathways, including upregulation of Gsto2, encoding glutathione S-transferase omega-2 (GSTO2). Selectively reducing Gsto2 in iSPNs in vivo effectively prevented dopaminergic dysfunction and halted the onset and progression of hyperkinetic symptoms. This study uncovers a functional link between altered iSPN BDNF-TrkB signalling, glutathione–ascorbate metabolism and hyperdopaminergic state, underscoring the vital role of GSTO2 in maintaining dopamine balance.

确定神经退行性疾病的初始触发事件对于开发预防性疗法至关重要。在亨廷顿舞蹈症 （HD） 中，多巴胺痛——可能是由受影响最严重的神经元——间接途径棘突投射神经元 （iSPN） 的功能障碍引发的——被认为会诱发运动亢进，这是一种早期的 HD 症状。然而，这种变化是如何产生并导致 HD 发病机制的尚不清楚。在这里，我们证明小鼠 Ntrk2/Trkb 缺失对 iSPNs 功能的遗传破坏导致纹状体多巴胺和中脑多巴胺能神经元增加，先于多动功能障碍。症状前阶段 iSPNs 的转录组学分析显示代谢途径失调，包括编码谷胱甘肽 S-转移酶 omega-2 （GSTO2） 的 Gsto2 上调。选择性降低体内 iSPNs 中的 Gsto2 可有效预防多巴胺能功能障碍并阻止多动症状的发生和发展。本研究揭示了改变的 iSPN BDNF-TrkB 信号传导、谷胱甘肽-抗坏血酸代谢和高多巴胺能状态之间的功能联系，强调了 GSTO2 在维持多巴胺平衡中的重要作用。