Ozawa Yoko, Kurihara Toshihide, Tsubota Kazuo, Okano Hideyuki
Laboratory of Retinal Cell Biology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
J Ophthalmol. 2011;2011:506137. doi: 10.1155/2011/506137. Epub 2010 Nov 7.
Understanding pathogenesis at the molecular level is the first step toward developing new therapeutic approaches. Here, we review the molecular mechanisms of visual dysfunction in two common diseases, innate chorioretinal inflammation and diabetic retinopathy, and the role of the ubiquitin-proteasome system (UPS) in both processes. In innate chorioretinal inflammation, interleukin-6 family ligands induce STAT3 activation in photoreceptors, which causes UPS-mediated excessive degradation of the visual substance, rhodopsin. In diabetic retinopathy, angiotensin II type 1 receptor (AT1R) signaling activates ERK in the inner layers of the retina, causing UPS-mediated excessive degradation of the synaptic vesicle protein, synaptophysin. This latter effect may decrease synaptic activity, in turn adversely affecting neuronal survival. Both mechanisms involve increased UPS activity and the subsequent excessive degradation of a protein required for visual function. Finally, we review the therapeutic potential of regulating the UPS to protect tissue function, citing examples from clinical applications in other medical fields.
在分子水平上理解发病机制是开发新治疗方法的第一步。在此，我们综述两种常见疾病——先天性脉络膜视网膜炎症和糖尿病性视网膜病变中视觉功能障碍的分子机制，以及泛素 - 蛋白酶体系统（UPS）在这两个过程中的作用。在先天性脉络膜视网膜炎症中，白细胞介素 - 6家族配体诱导光感受器中的STAT3激活，这导致UPS介导的视觉物质视紫红质的过度降解。在糖尿病性视网膜病变中，1型血管紧张素II受体（AT1R）信号传导激活视网膜内层的ERK，导致UPS介导的突触小泡蛋白突触素的过度降解。后一种效应可能会降低突触活性，进而对神经元存活产生不利影响。这两种机制都涉及UPS活性增加以及随后视觉功能所需蛋白质的过度降解。最后，我们以其他医学领域的临床应用为例，综述调节UPS以保护组织功能的治疗潜力。
