Roman Kaitlyn M, Dinasarapu Ashok R, Cherian Suraj, Fan Xueliang, Donsante Yuping, Aravind Nivetha, Chan C Savio, Jinnah H A, Hess Ellen J
Department of Pharmacology and Chemical Biology, Emory University, Atlanta, GA, USA.
Department of Neurology, Emory University, Atlanta, GA, USA.
Neurobiol Dis. 2025 Aug;212:106981. doi: 10.1016/j.nbd.2025.106981. Epub 2025 May 28.
Abnormal dopamine neurotransmission and striatal dysfunction is implicated in many forms of dystonia, yet the underlying molecular processes remain unknown. Here, we identified thousands of dysregulated genes within striatal spiny projection neuron (SPN) subtypes in a genetic mouse model of DOPA-responsive dystonia (DRD), which is caused by gene defects that reduce dopamine neurotransmission. Although changes in mRNA expression were unique to each SPN subtype, abnormal glutamatergic signaling was implicated in each SPN subtype. Indeed, both AMPA and NMDA receptor-mediated currents were enhanced in direct SPNs but diminished in indirect SPNs in DRD mice. The pattern of mRNA dysregulation was distinct from parkinsonism where the dopamine deficit occurs in adults, suggesting that the phenotypic outcome is dependent on both the timing of the dopaminergic deficit and the SPN-specific adaptions. By leveraging these disease-specific molecular signatures, we identified LRRK2 inhibition, among other mechanisms, as a novel therapeutic target for dystonia.
异常的多巴胺神经传递和纹状体功能障碍与多种形式的肌张力障碍有关，但其潜在的分子过程仍不清楚。在这里，我们在多巴反应性肌张力障碍（DRD）的遗传小鼠模型中，确定了纹状体棘状投射神经元（SPN）亚型内数千个失调基因，DRD由减少多巴胺神经传递的基因缺陷引起。虽然mRNA表达的变化对每个SPN亚型都是独特的，但异常的谷氨酸能信号传导与每个SPN亚型有关。事实上，在DRD小鼠中，AMPA和NMDA受体介导的电流在直接SPN中增强，但在间接SPN中减弱。mRNA失调模式与成人出现多巴胺缺乏的帕金森病不同，这表明表型结果取决于多巴胺能缺乏的时间和SPN特异性适应。通过利用这些疾病特异性分子特征，我们确定了LRRK2抑制等机制作为肌张力障碍的新治疗靶点。
