Biotechnology and Biotherapy team, ICM Brain and Spine Institute, Sorbonne University/INSERM U 1127/CNRS UMR 7225, CHU Pitié-Salpêtrière, Paris, France (Galet, Ingallinesi, Pegon, Do Thi, Ravassard, Faucon Biguet, Meloni).
J Psychiatry Neurosci. 2021 Jan 4;46(1):E44-E55. doi: 10.1503/jpn.190171.
In addition to motor disability, another characteristic feature of Parkinson disease is the early appearance of psychiatric symptoms, including apathy, depression, anxiety and cognitive deficits; treatments for these symptoms are limited by the development of adverse effects such as impulse-control disorders. In this context, we investigated the orphan G protein-coupled receptor 88 (GPR88) as a novel therapeutic target.
We used lentiviral-mediated expression of specifically designed microRNA to knock down Gpr88 in a translational male rat model of early Parkinson disease obtained by dopamine loss in the dorsolateral striatum as a result of 6-hydroxydopamine lesions. We evaluated the impact of Gpr88 knockdown on the Parkinson disease model using behavioural, immunohistochemical and in situ hybridization studies.
Knockdown of Gpr88 in associative territories of the dorsal striatum efficiently reduced alterations in mood, motivation and cognition through modulation of the regulator of the G-protein signalling 4 and of the truncated splice variant of the FosB transcription factor. Knockdown of Gpr88 also reduced allostatic changes in striatal activity markers that may be related to patterns observed in patients and that provide support for an "overload" hypothesis for the etiology of the psychiatric symptoms of Parkinson disease.
Behavioural tests assessing specific cognitive and motivational parameters are needed to further characterize the effects of the lesion and of Gpr88 knockdown in early-stage and advanced Parkinson disease models, presenting more extensive dopamine loss. Additional studies focusing on the direct and indirect striatal output pathways are also required, because little is known about the signalling pathways regulated by GPR88 in different striatal cell types.
GPR88 may constitute a highly relevant target for the treatment of the psychiatric symptoms of Parkinson disease.
除了运动障碍外，帕金森病的另一个特征是早期出现精神症状，包括冷漠、抑郁、焦虑和认知缺陷；这些症状的治疗受到冲动控制障碍等不良反应发展的限制。在这种情况下，我们研究了孤儿 G 蛋白偶联受体 88（GPR88）作为一个新的治疗靶点。
我们使用慢病毒介导的特异性设计 microRNA 表达来敲低雄性翻译大鼠模型中背外侧纹状体多巴胺缺失引起的早期帕金森病模型中的 Gpr88。我们使用行为学、免疫组织化学和原位杂交研究来评估 Gpr88 敲低对帕金森病模型的影响。
Gpr88 在背侧纹状体的联想区域的敲低通过调节 G 蛋白信号转导调节因子 4 和 FosB 转录因子的截断剪接变体有效地减少了情绪、动机和认知的改变。Gpr88 的敲低还减少了纹状体活性标志物的适应变化，这些变化可能与患者观察到的模式有关，并为帕金森病精神症状的病因提供了“过载”假说的支持。
需要进行评估特定认知和动机参数的行为测试，以进一步表征病变和 Gpr88 敲低对早期和晚期帕金森病模型的影响，这些模型表现出更广泛的多巴胺缺失。还需要更多关注直接和间接纹状体输出途径的研究，因为对于不同纹状体细胞类型中 GPR88 调节的信号通路知之甚少。
GPR88 可能是治疗帕金森病精神症状的一个非常相关的靶点。
