Santini Emanuela, Heiman Myriam, Greengard Paul, Valjent Emmanuel, Fisone Gilberto
Department of Neuroscience, Karolinska Institutet, Retzius väg 8, 171 77 Stockholm, Sweden.
Sci Signal. 2009 Jul 21;2(80):ra36. doi: 10.1126/scisignal.2000308.
Parkinson's disease (PD), a disorder caused by degeneration of the dopaminergic input to the basal ganglia, is commonly treated with l-DOPA. Use of this drug, however, is severely limited by motor side effects, or dyskinesia. We show that administration of l-DOPA in a mouse model of Parkinsonism led to dopamine D1 receptor-mediated activation of the mammalian target of rapamycin (mTOR) complex 1 (mTORC1), which is implicated in several forms of synaptic plasticity. This response occurred selectively in the GABAergic medium spiny neurons that project directly from the striatum to the output structures of the basal ganglia. The l-DOPA-mediated activation of mTORC1 persisted in mice that developed dyskinesia. Moreover, the mTORC1 inhibitor rapamycin prevented the development of dyskinesia without affecting the therapeutic efficacy of l-DOPA. Thus, the mTORC1 signaling cascade represents a promising target for the design of anti-Parkinsonian therapies.
帕金森病（PD）是一种由基底神经节多巴胺能输入退化引起的疾病，通常用左旋多巴进行治疗。然而，这种药物的使用受到运动副作用或运动障碍的严重限制。我们发现，在帕金森病小鼠模型中给予左旋多巴会导致多巴胺D1受体介导的雷帕霉素哺乳动物靶标（mTOR）复合物1（mTORC1）的激活，这与多种形式的突触可塑性有关。这种反应选择性地发生在从纹状体直接投射到基底神经节输出结构的GABA能中型多棘神经元中。左旋多巴介导的mTORC1激活在出现运动障碍的小鼠中持续存在。此外，mTORC1抑制剂雷帕霉素可预防运动障碍的发生，而不影响左旋多巴的治疗效果。因此，mTORC1信号级联代表了抗帕金森病治疗设计的一个有前景的靶点。
