Mak Heather K, Yung Jasmine S Y, Weinreb Robert N, Ng Shuk Han, Cao Xu, Ho Tracy Y C, Ng Tsz Kin, Chu Wai Kit, Yung Wing Ho, Choy Kwong Wai, Wang Chi Chiu, Lee Tin Lap, Leung Christopher Kai-Shun
Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, Hong Kong, PRC.
Hamilton Glaucoma Center, Shiley Eye Institute, University of California, San Diego, La Jolla, CA, USA; Department of Ophthalmology, University of California, San Diego, La Jolla, CA, USA.
Mol Ther Nucleic Acids. 2020 Sep 4;21:251-263. doi: 10.1016/j.omtn.2020.05.031. Epub 2020 Jun 1.
Irreversible blindness from glaucoma and optic neuropathies is attributed to retinal ganglion cells (RGCs) losing the ability to regenerate axons. While several transcription factors and proteins have demonstrated enhancement of axon regeneration after optic nerve injury, mechanisms contributing to the age-related decline in axon regenerative capacity remain elusive. In this study, we show that microRNAs are differentially expressed during RGC development and identify microRNA-19a (miR-19a) as a heterochronic marker; developmental decline of miR-19a relieves suppression of phosphatase and tensin homolog (PTEN), a key regulator of axon regeneration, and serves as a temporal indicator of decreasing axon regenerative capacity. Intravitreal injection of miR-19a promotes axon regeneration after optic nerve crush in adult mice, and it increases axon extension in RGCs isolated from aged human donors. This study uncovers a previously unrecognized involvement of the miR-19a-PTEN axis in RGC axon regeneration, and it demonstrates therapeutic potential of microRNA-mediated restoration of axon regenerative capacity in optic neuropathies.
青光眼和视神经病变导致的不可逆失明归因于视网膜神经节细胞（RGCs）失去轴突再生能力。虽然几种转录因子和蛋白质已证明可增强视神经损伤后的轴突再生，但导致轴突再生能力随年龄下降的机制仍不清楚。在本研究中，我们表明微小RNA在RGC发育过程中差异表达，并确定微小RNA-19a（miR-19a）为异时性标志物；miR-19a的发育性下降减轻了对轴突再生关键调节因子磷酸酶和张力蛋白同源物（PTEN）的抑制，并作为轴突再生能力下降的时间指标。玻璃体内注射miR-19a可促进成年小鼠视神经挤压伤后的轴突再生，并增加从老年人类供体分离的RGCs中的轴突延伸。本研究揭示了miR-19a-PTEN轴在RGC轴突再生中以前未被认识的作用，并证明了微小RNA介导的恢复视神经病变中轴突再生能力的治疗潜力。
