视神经损伤

    MicroRNA-based therapeutics for optic neuropathy: opportunities and challenges
  • Figure 1|Illustration of the microRNA-19a/PTEN axis in regulation of axon regenerative capacity of retinal ganglion cells (RGCs).

    While evidence of miRNA-mediated alleviation of RGC apoptosis in animal models of optic neuropathies demonstrates the therapeutic potential of miRNAs, whether miRNAs govern the intrinsic molecular events that lead to the developmental loss of axon regenerative capacity in RGCs remains elusive. As RGCs make up less than 5% of retinal cells, previous miRNA profiling studies using whole retinas can hardly inform the repertoire of miRNA expression in RGCs. In a recent study, we characterized the expression of miRNA profiles in purified rodent RGCs at different developmental ages (E21, P6, and P30) using microarray and found that 76 miRNAs were differentially expressed from embryonic to adult ages, which included five of six members of the miR-17/92 cluster (Mak et al., 2020). In this miRNA cluster, miR-19a was significantly downregulated in aged RGCs and predicted to target PTEN, a known inhibitor of optic nerve regeneration. The study identifies the miR-19a/PTEN axis to be a heterochronic marker for axon regenerative capacity in RGCs; developmental loss in ability to regenerate axons is connected to an intrinsic decline in miR-19a over time, relieving PTEN suppression which contributes to inhibition of axon regeneration (Figure 1). Increasing intracellular levels of miR-19a significantly enhanced axon outgrowth of postnatal rodent RGCs cultured in microfluidic chambers; whereas decreasing the endogenous levels of miR-19a showed significantly reduced axon outgrowth. Axon outgrowth was similarly augmented in RGCs purified from 69- and 75-year-old human donors supplemented with miR-19a. In a mouse model of optic nerve crush, replenishing miR-19a in adult RGCs via AAV-based delivery improved RGC survival and promoted axon regeneration. miRNA-mediated PTEN suppression, however, did not completely remove intracellular PTEN. The fact that miRNAs are fine tuners of gene expression and that the proportion of RGCs with upregulation of miR-19a depends on the transduction efficiency of AAV explains the weaker axon regeneration by miR-19a compared with PTEN knockout transgenic animals after optic nerve injury. Nevertheless, our findings underscore the potential of manipulating the levels of miRNA to rejuvenate the intrinsic capacity of axon regeneration for treatment of optic neuropathies. 

    点击此处查看全文

  • 发布日期: 2021-03-20  浏览: 593
分享