State Key Laboratory of Ophthalmology, Optometry and Visual Science, The Eye Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325027, China; Vascular Biology Program, Department of Surgery, Boston Children's Hospital, Boston, MA, 02115, USA.
Vascular Biology Program, Department of Surgery, Boston Children's Hospital, Boston, MA, 02115, USA.
Neuropharmacology. 2019 Apr;148:96-106. doi: 10.1016/j.neuropharm.2018.12.029. Epub 2018 Dec 27.
Neurodegenerative diseases affect millions of people worldwide. Optic neuropathies are the most commonly occurring neurodegenerative diseases, characterized by progressive retinal ganglion cell (RGC) degeneration. We recently reported that Prominin-1, a protein found on the surface of stem cells, interacts with VEGF and enhances its activity. VEGF is known to have various protective roles in the nervous system. Subsequently, we have developed a 12-mer peptide derived from Prominin-1, named PR1P, and investigated its effects on neuronal survival of damaged RGCs in a rat model of optic nerve crush (ONC). PR1P prevented RGC apoptosis resulting in improvement of retinal function in the rat ONC model. PR1P treatment significantly increased phosphorylation of ERK and AKT and expression its downstream proteins c-fos and Egr-1 in the retina. Additionally, PR1P beneficially increased the MMP-9/TIMP-1 ratio and promoted glial activation in the retina of ONC rats. Thus, PR1P displayed neuroprotective effects through enhanced VEGF-driven neuronal survival and reconstruction of the extracellular environment in ONC model. Our data indicate that PR1P may be a promising new clinical candidate for the treatment of neurodegenerative diseases.
神经退行性疾病影响着全球数百万人。视神经病变是最常见的神经退行性疾病，其特征是视网膜神经节细胞（RGC）进行性退化。我们最近报道，Prominin-1 是一种存在于干细胞表面的蛋白质，它与 VEGF 相互作用并增强其活性。已知 VEGF 在神经系统中具有多种保护作用。随后，我们开发了一种源自 Prominin-1 的 12 肽，命名为 PR1P，并在视神经挤压（ONC）大鼠模型中研究了其对受损 RGC 神经元存活的影响。PR1P 可防止 RGC 凋亡，从而改善大鼠 ONC 模型中的视网膜功能。PR1P 治疗可显著增加视网膜中 ERK 和 AKT 的磷酸化及其下游蛋白 c-fos 和 Egr-1 的表达。此外，PR1P 可有益地增加 MMP-9/TIMP-1 比值，并促进 ONC 大鼠视网膜中的神经胶质激活。因此，PR1P 通过增强 VEGF 驱动的神经元存活和 ONC 模型中细胞外环境的重建来发挥神经保护作用。我们的数据表明，PR1P 可能是治疗神经退行性疾病的一种有前途的新临床候选药物。
