Department of Surgical Sciences, University of Wisconsin-Madison, Madison, WI, USA.
Department of Ophthalmology and Visual Sciences, University of Wisconsin-Madison, 1300 University Avenue, Madison, WI, 53706, USA.
Mol Neurobiol. 2020 Jun;57(6):2620-2638. doi: 10.1007/s12035-020-01910-9. Epub 2020 Apr 7.
Glaucoma, a multifactorial neurodegenerative disease characterized by progressive loss of retinal ganglion cells and their axons in the optic nerve, is a leading cause of irreversible vision loss. Intraocular pressure (IOP) is a risk factor for axonal damage, which initially occurs at the optic nerve head (ONH). Complex cellular and molecular mechanisms involved in the pathogenesis of glaucomatous optic neuropathy remain unclear. Here we define early molecular events in the ONH in an inherited large animal glaucoma model in which ONH structure resembles that of humans. Gene expression profiling of ONH tissues from rigorously phenotyped feline subjects with early-stage glaucoma and precisely age-matched controls was performed by RNA-sequencing (RNA-seq) analysis and complementary bioinformatic approaches applied to identify molecular processes and pathways of interest. Immunolabeling supported RNA-seq findings while providing cell-, region-, and disease stage-specific context in the ONH in situ. Transcriptomic evidence for cell proliferation and immune/inflammatory responses is identifiable in early glaucoma, soon after IOP elevation and prior to morphologically detectable axon loss, in this large animal model. In particular, proliferation of microglia and oligodendrocyte precursor cells is a prominent feature of early-stage, but not chronic, glaucoma. ONH microgliosis is a consistent hallmark in both early and chronic stages of glaucoma. Molecular pathways and cell type-specific responses strongly implicate toll-like receptor and NF-κB signaling in early glaucoma pathophysiology. The current study provides critical insights into molecular pathways, highly dependent on cell type and sub-region in the ONH even prior to irreversible axon degeneration in glaucoma.
青光眼是一种多因素的神经退行性疾病，其特征是视网膜神经节细胞及其轴突在视神经中进行性丧失，是不可逆视力丧失的主要原因。眼内压（IOP）是轴突损伤的一个危险因素，这种损伤最初发生在视神经头（ONH）。青光眼视神经病变发病机制中涉及的复杂细胞和分子机制仍不清楚。在这里，我们在一种遗传性大动物青光眼模型中定义了 ONH 的早期分子事件，该模型中的 ONH 结构与人相似。通过 RNA 测序（RNA-seq）分析和互补的生物信息学方法对来自早期青光眼和精确年龄匹配对照的严格表型猫科动物对象的 ONH 组织进行基因表达谱分析，以识别感兴趣的分子过程和途径。免疫标记支持 RNA-seq 发现，同时提供了 ONH 原位中的细胞、区域和疾病阶段特异性背景。在这个大动物模型中，转录组证据表明细胞增殖和免疫/炎症反应可在眼压升高后不久，在形态学上可检测到轴突丢失之前，在早期青光眼时识别。特别是小胶质细胞和少突胶质细胞前体细胞的增殖是早期而非慢性青光眼的一个突出特征。ONH 小胶质细胞增生是青光眼早期和慢性阶段的一致特征。分子途径和细胞类型特异性反应强烈表明，在青光眼的早期发病机制中，Toll 样受体和 NF-κB 信号通路起着重要作用。本研究提供了对分子途径的重要见解，这些途径高度依赖于 ONH 中的细胞类型和亚区，甚至在青光眼不可逆轴突退化之前也是如此。
