帕金森病中3型代谢型谷氨酸受体的临床前和临床研究。
Preclinical and clinical study on type 3 metabotropic glutamate receptors in Parkinson's disease.
作者信息
Di Menna Luisa, Alborghetti Marika, De Bartolo Maria Ilenia, Borro Marina, Gentile Giovanna, Zinni Manuela, Bologna Matteo, Cutrona Carolina, D'Errico Giovanna, Imbriglio Tiziana, Bucci Domenico, Merlo Sara, Ginerete Roxana Paula, Orlando Rosamaria, Carrillo Federica, Fortunato Giorgio, Cannella Milena, Sortino Maria Angela, Pansiot Julien, Baud Olivier, Nicoletti Ferdinando, Bruno Valeria, Simmaco Maurizio, Pontieri Francesco Ernesto, Bianchini Edoardo, Rinaldi Domiziana, de Curtis Amalia, De Gaetano Giovanni, Iacoviello Licia, Esposito Teresa, Berardelli Alfredo, Battaglia Giuseppe
机构信息
Department of Molecular Pathology, IRCCS Neuromed, Pozzilli, Italy.
Departments of Human Neurosciences, Sapienza University of Rome, Rome, Italy.
出版信息
NPJ Parkinsons Dis. 2025 Jan 4;11(1):9. doi: 10.1038/s41531-024-00860-6.
Metabotropic glutamate (mGlu) receptors are candidate drug targets for therapeutic intervention in Parkinson's disease (PD). Here we focused on mGlu3, a receptor subtype involved in synaptic regulation and neuroinflammation. mGlu3 mice showed an enhanced nigro-striatal damage and microglial activation in response to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Expression of genes encoding anti-inflammatory proteins and neuroprotective factors was reduced in the striatum of MPTP-treated mGlu3 mice. We also examined polymorphic variants of GRM3 (the mGlu3 receptor encoding gene) in 723 PD patients and 826 healthy controls. Two GRM3 haplotypes were associated with PD, and gene variants correlated with motor and non-motor signs. Interestingly, PD patients carrying each of the two haplotypes showed an impaired cortical plasticity in the paired associated stimulation paradigm of magnetic transcranial stimulation. These findings suggest that mGlu3 receptors are neuroprotective in mouse models of parkinsonism and shape mechanisms of cortical plasticity in PD.
代谢型谷氨酸（mGlu）受体是帕金森病（PD）治疗干预的候选药物靶点。在此，我们聚焦于mGlu3，这是一种参与突触调节和神经炎症的受体亚型。mGlu3基因敲除小鼠对1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）表现出增强的黑质纹状体损伤和小胶质细胞激活。在MPTP处理的mGlu3基因敲除小鼠的纹状体中，编码抗炎蛋白和神经保护因子的基因表达降低。我们还在723例PD患者和826例健康对照中检测了GRM3（mGlu3受体编码基因）的多态性变体。两种GRM3单倍型与PD相关，且基因变体与运动和非运动症状相关。有趣的是，携带这两种单倍型之一的PD患者在磁刺激经颅刺激的配对关联刺激范式中表现出皮质可塑性受损。这些发现表明，mGlu3受体在帕金森病小鼠模型中具有神经保护作用，并影响PD患者的皮质可塑性机制。
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