Department of Ophthalmology, University of California San Francisco, San Francisco, CA 94158, USA.
Department of Ophthalmology, University of California San Francisco, San Francisco, CA 94158, USA.
Cell Rep. 2023 Sep 26;42(9):113038. doi: 10.1016/j.celrep.2023.113038. Epub 2023 Aug 23.
Chronic neurodegeneration and acute injuries lead to neuron losses via diverse processes. We compared retinal ganglion cell (RGC) responses between chronic glaucomatous conditions and the acute injury model. Among major RGC subclasses, αRGCs and intrinsically photosensitive RGCs (ipRGCs) preferentially survive glaucomatous conditions, similar to findings in the retina subject to axotomy. Focusing on an αRGC intrinsic factor, Osteopontin (secreted phosphoprotein 1 [Spp1]), we found an ectopic neuronal expression of Osteopontin (Spp1) in other RGCs subject to glaucomatous conditions. This contrasted with the Spp1 downregulation subject to axotomy. αRGC-specific Spp1 elimination led to significant αRGC loss, diminishing their resiliency. Spp1 overexpression led to robust neuroprotection of susceptible RGC subclasses under glaucomatous conditions. In contrast, Spp1 overexpression did not significantly protect RGCs subject to axotomy. Additionally, SPP1 marked adult human RGC subsets with large somata and SPP1 expression in the aqueous humor correlated with glaucoma severity. Our study reveals Spp1's role in mediating neuronal resiliency in glaucoma.
慢性神经退行性变和急性损伤通过不同的过程导致神经元丢失。我们比较了慢性青光眼状态和急性损伤模型之间的视网膜神经节细胞 (RGC) 反应。在主要的 RGC 亚类中，αRGC 和内在光敏感 RGC (ipRGC) 优先在青光眼条件下存活，这与在经历轴突切断的视网膜中的发现相似。我们关注αRGC 的内在因素骨桥蛋白 (分泌磷蛋白 1[Spp1])，发现在青光眼条件下，其他 RGC 中存在骨桥蛋白 (Spp1) 的异位神经元表达。这与轴突切断时 Spp1 的下调形成对比。αRGC 特异性 Spp1 消除导致显著的 αRGC 丢失，降低了它们的弹性。Spp1 的过表达导致易感 RGC 亚类在青光眼条件下的强大神经保护作用。相比之下，Spp1 的过表达并不能显著保护经历轴突切断的 RGC。此外，SPP1 标记了具有大胞体的成年人类 RGC 亚群，房水中的 SPP1 表达与青光眼的严重程度相关。我们的研究揭示了 Spp1 在介导青光眼神经元弹性中的作用。
