Sicot Géraldine, Servais Laurent, Dinca Diana M, Leroy Axelle, Prigogine Cynthia, Medja Fadia, Braz Sandra O, Huguet-Lachon Aline, Chhuon Cerina, Nicole Annie, Gueriba Noëmy, Oliveira Ruan, Dan Bernard, Furling Denis, Swanson Maurice S, Guerrera Ida Chiara, Cheron Guy, Gourdon Geneviève, Gomes-Pereira Mário
Laboratory CTGDM, Inserm UMR1163, 75015 Paris, France; Institut Imagine, Université Paris Descartes-Sorbonne Paris Cité, 75015 Paris, France.
Institut I-Motion, Hôpital Armand Trousseau, 75012 Paris, France.
Cell Rep. 2017 Jun 27;19(13):2718-2729. doi: 10.1016/j.celrep.2017.06.006.
Brain function is compromised in myotonic dystrophy type 1 (DM1), but the underlying mechanisms are not fully understood. To gain insight into the cellular and molecular pathways primarily affected, we studied a mouse model of DM1 and brains of adult patients. We found pronounced RNA toxicity in the Bergmann glia of the cerebellum, in association with abnormal Purkinje cell firing and fine motor incoordination in DM1 mice. A global proteomics approach revealed downregulation of the GLT1 glutamate transporter in DM1 mice and human patients, which we found to be the result of MBNL1 inactivation. GLT1 downregulation in DM1 astrocytes increases glutamate neurotoxicity and is detrimental to neurons. Finally, we demonstrated that the upregulation of GLT1 corrected Purkinje cell firing and motor incoordination in DM1 mice. Our findings show that glial defects are critical in DM1 brain pathophysiology and open promising therapeutic perspectives through the modulation of glutamate levels.
1型强直性肌营养不良（DM1）患者存在脑功能受损的情况，但其潜在机制尚未完全明确。为深入了解主要受影响的细胞和分子途径，我们研究了DM1小鼠模型及成年患者的大脑。我们发现，DM1小鼠小脑的伯格曼胶质细胞存在明显的RNA毒性，同时伴有浦肯野细胞放电异常和精细运动不协调。一种全局蛋白质组学方法显示，DM1小鼠和人类患者中GLT1谷氨酸转运体下调，我们发现这是MBNL1失活的结果。DM1星形胶质细胞中GLT1下调会增加谷氨酸神经毒性，并对神经元有害。最后，我们证明上调GLT1可纠正DM1小鼠的浦肯野细胞放电和运动不协调。我们的研究结果表明，胶质细胞缺陷在DM1脑病理生理学中至关重要，并通过调节谷氨酸水平开辟了有前景的治疗前景。
