Soto Ileana, Oglesby Ericka, Buckingham Brian P, Son Janice L, Roberson Elisha D O, Steele Michael R, Inman Denise M, Vetter Monica L, Horner Philip J, Marsh-Armstrong Nicholas
Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
J Neurosci. 2008 Jan 9;28(2):548-61. doi: 10.1523/JNEUROSCI.3714-07.2008.
Little is known about molecular changes occurring within retinal ganglion cells (RGCs) before their death in glaucoma. Taking advantage of the fact that gamma-synuclein (Sncg) mRNA is expressed specifically and highly in adult mouse RGCs, we show in the DBA/2J mouse model of glaucoma that there is not only a loss of cells expressing this gene, but also a downregulation of gene expression of Sncg and many other genes within large numbers of RGCs. This downregulation of gene expression within RGCs occurs together with reductions in FluoroGold (FG) retrograde transport. Surprisingly, there are also large numbers of Sncg-expressing cells without any FG labeling, and among these many that have a marker previously associated with disconnected RGCs, accumulation of phosphorylated neurofilaments in their somas. These same diseased retinas also have large numbers of RGCs that maintain the intraocular portion while losing the optic nerve portion of their axons, and these disconnected axons terminate within the optic nerve head. Our data support the view that RGC degeneration in glaucoma has two separable stages: the first involves atrophy of RGCs, whereas the second involves an insult to axons, which causes the degeneration of axon portions distal to the optic nerve head but does not cause the immediate degeneration of intraretinal portions of axons or the immediate death of RGCs.
关于青光眼患者视网膜神经节细胞（RGCs）在死亡前发生的分子变化，我们知之甚少。利用γ-突触核蛋白（Sncg）mRNA在成年小鼠RGCs中特异性高表达这一事实，我们在DBA/2J青光眼小鼠模型中发现，不仅表达该基因的细胞数量减少，而且大量RGCs内Sncg及许多其他基因的表达也下调。RGCs内基因表达的这种下调与荧光金（FG）逆行运输的减少同时发生。令人惊讶的是，也有大量表达Sncg的细胞没有任何FG标记，其中许多细胞具有先前与断开连接的RGCs相关的标记物，其胞体中有磷酸化神经丝的积累。这些患病视网膜中也有大量RGCs，它们保留了眼内部分的轴突，却失去了视神经部分的轴突，这些断开连接的轴突在视神经乳头内终止。我们的数据支持这样一种观点，即青光眼患者RGCs的退化有两个可分离的阶段：第一个阶段涉及RGCs的萎缩，而第二个阶段涉及对轴突的损伤，这会导致视神经乳头远端轴突部分的退化，但不会导致轴突视网膜内部分的立即退化或RGCs的立即死亡。
