Department of Ophthalmology and Visual Sciences, Vanderbilt Eye Institute, Vanderbilt University Medical Center, AA7103 MCN/VUIIS, 1161 21st Ave. S, Nashville, TN, 37232, USA.
Mol Neurodegener. 2021 Jun 5;16(1):36. doi: 10.1186/s13024-021-00459-y.
Early challenges to axonal physiology, active transport, and ultrastructure are endemic to age-related neurodegenerative disorders, including those affecting the optic nerve. Chief among these, glaucoma causes irreversible vision loss through sensitivity to intraocular pressure (IOP) that challenges retinal ganglion cell (RGC) axons, which comprise the optic nerve. Early RGC axonopathy includes distal to proximal progression that implicates a slow form of Wallerian degeneration. In multiple disease models, including inducible glaucoma, expression of the slow Wallerian degeneration (Wld) allele slows axon degeneration and confers protection to cell bodies.
Using an inducible model of glaucoma along with whole-cell patch clamp electrophysiology and morphological analysis, we tested if Wld also protects RGC light responses and dendrites and, if so, whether this protection depends upon RGC type. We induced glaucoma in young and aged mice to determine if neuroprotection by Wld on anterograde axonal transport and spatial contrast acuity depends on age.
We found Wld protects dendritic morphology and light-evoked responses of RGCs that signal light onset (αON-Sustained) during IOP elevation. However, IOP elevation significantly reduces dendritic complexity and light responses of RGCs that respond to light offset (αOFF-Sustained) regardless of Wld. As expected, Wld preserves anterograde axon transport and spatial acuity in young adult mice, but its protection is significantly limited in aged mice.
The efficacy of Wld in conferring protection to neurons and their axons varies by cell type and diminishes with age.
轴突生理学、主动运输和超微结构的早期挑战是与年龄相关的神经退行性疾病所固有的，包括影响视神经的疾病。其中最主要的是青光眼，由于对眼压（IOP）的敏感性，导致视网膜神经节细胞（RGC）轴突不可逆转的视力丧失，而这些轴突构成了视神经。早期 RGC 轴突病变包括从远端到近端的进展，这涉及到一种缓慢的沃勒变性形式。在多种疾病模型中，包括诱导性青光眼，缓慢沃勒变性（Wld）等位基因的表达可减缓轴突变性，并对细胞体提供保护。
我们使用诱导性青光眼模型，结合全细胞膜片钳电生理学和形态分析，测试 Wld 是否也能保护 RGC 的光反应和树突，如果是，这种保护是否取决于 RGC 类型。我们在年轻和老年小鼠中诱导青光眼，以确定 Wld 对顺行轴突运输和空间对比敏锐度的神经保护是否取决于年龄。
我们发现 Wld 可保护 RGC 的树突形态和光诱发反应，这些反应在眼压升高期间信号光的起始（αON-Sustained）。然而，眼压升高显著降低了对光结束（αOFF-Sustained）反应的 RGC 的树突复杂性和光反应，而与 Wld 无关。正如预期的那样，Wld 在年轻成年小鼠中可保护顺行轴突运输和空间敏锐度，但在老年小鼠中其保护作用显著受限。
Wld 对神经元及其轴突的保护作用因其细胞类型而异，并随着年龄的增长而减弱。
