Department of Neuroscience, Centre for Addiction and Mental Health Toronto, Ontario, Canada, M5T 1R8.
Toronto General Research Institute, University Health Network Toronto, Ontario, Canada.
Ann Clin Transl Neurol. 2015 Apr;2(4):388-400. doi: 10.1002/acn3.182. Epub 2015 Feb 19.
Multiple sclerosis (MS) is the most common disabling neurological disease of young adults. The pathophysiological mechanism of MS remains largely unknown and no cure is available. Current clinical treatments for MS modulate the immune system, with the rationale that autoimmunity is at the core of MS pathophysiology.
Experimental autoimmune encephalitis (EAE) was induced in mice with MOG35-55 and clinical scoring was performed to monitor signs of paralysis. EAE mice were injected intraperitoneally with TAT-fusion peptides daily from day 10 until day 30 after immunization, and their effects were measured at day 17 or day 30.
We report a novel target for the development of MS therapy, which aimed at blocking glutamate-mediated neurotoxicity through targeting the interaction between the AMPA (2-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl) propanoic acid) receptor and an interacting protein. We found that protein complex composed of the GluR2 subunit of AMPA receptors and GAPDH (glyceraldehyde-3-phosphate dehydrogenase) was present at significantly higher levels in postmortem tissue from MS patients and in EAE mice, an animal model for MS. Next, we developed a peptide that specifically disrupts the GluR2 -GAPDH complex. This peptide greatly improves neurological function in EAE mice, reduces neuron death, rescues demyelination, increases oligodendrocyte survival, and reduces axonal damage in the spinal cords of EAE mice. More importantly, our peptide has no direct suppressive effect on naive T-cell responses or basal neurotransmission.
The GluR2 -GAPDH complex represents a novel therapeutic target for the development of medications for MS that work through a different mechanism than existing treatments.
多发性硬化症（MS）是最常见的青年期致残性神经疾病。MS 的病理生理机制在很大程度上尚不清楚，也没有治愈方法。目前用于 MS 的临床治疗方法调节免疫系统，其理论基础是自身免疫是 MS 病理生理学的核心。
用 MOG35-55 在小鼠中诱导实验性自身免疫性脑脊髓炎（EAE），并进行临床评分以监测瘫痪迹象。EAE 小鼠从免疫后第 10 天至第 30 天每天腹腔注射 TAT 融合肽，并在第 17 天或第 30 天测量其效果。
我们报告了一种用于开发 MS 治疗的新靶标，该靶标旨在通过靶向 AMPA（2-氨基-3-（3-羟基-5-甲基异恶唑-4-基）丙酸）受体和相互作用蛋白之间的相互作用来阻断谷氨酸介导的神经毒性。我们发现，在 MS 患者和 EAE 小鼠（MS 的动物模型）的死后组织中，谷氨酸受体 GluR2 亚基和 GAPDH（甘油醛-3-磷酸脱氢酶）组成的蛋白复合物水平显著升高。接下来，我们开发了一种特异性破坏 GluR2-GAPDH 复合物的肽。该肽可极大地改善 EAE 小鼠的神经功能，减少神经元死亡，挽救脱髓鞘，增加少突胶质细胞存活，并减少 EAE 小鼠脊髓中的轴突损伤。更重要的是，我们的肽对幼稚 T 细胞反应或基础神经传递没有直接的抑制作用。
GluR2-GAPDH 复合物代表了一种用于开发 MS 药物的新治疗靶标，其作用机制与现有治疗方法不同。
