Department of Vision Sciences, Toronto Western Hospital, University Health Network, Toronto, Ontario, Canada.
Department of Vision Sciences, Toronto Western Hospital, University Health Network, Toronto, Ontario, Canada; Genetic and Molecular Epidemiology Unit, Department of Preventive Medicine and Public Health, University of Valencia School of Medicine, Valencia, Spain; Spanish Biomedical Research Center in Physiopathology of Obesity and Nutrition (CIBER), University of Valencia, Valencia, Spain.
Am J Pathol. 2014 Apr;184(4):1017-1029. doi: 10.1016/j.ajpath.2013.12.012. Epub 2014 Feb 5.
Retinal ganglion cells (RGCs), used as a common model of central nervous system injury, are particularly vulnerable to metabolic and oxidative damage. However, molecular mechanisms underlying this sensitivity have not been determined in vivo. PGC-1α (encoded by PPARGC1A) regulates adaptive metabolism and oxidative stress responses in a tissue- and cell-specific manner. Aberrant PGC-1α signaling is implicated in neurodegeneration, but the mechanism underlying its role in central nervous system injury remains unclear. We provide evidence from a mouse model that PGC-1α expression and activity are induced in adult retina in response to metabolic and oxidative challenge. Deletion of Ppargc1a dramatically increased RGC loss, in association with dysregulated expression of PGC-1α target metabolic and oxidative stress response genes, including Hmox1 (encoding HO-1), Tfam, and Vegfa. Vehicle-treated and naive Ppargc1a(-/-) mice also showed mild RGC loss, and surprisingly prominent and consistent retinal astrocyte reactivity. These cells critically regulate metabolic homeostasis in the inner retina. We show that PGC-1α signaling (not previously studied in glia) regulates detoxifying astrocyte responses to hypoxic and oxidative stresses. Finally, PGC-1α expression was modulated in the inner retina with age and in a model of chronic optic neuropathy. These data implicate PGC-1α signaling as an important regulator of astrocyte reactivity and RGC homeostasis to coordinate pathogenic susceptibility to metabolic and oxidative injury in the inner retina.
视网膜神经节细胞 (RGCs) 被用作中枢神经系统损伤的常见模型，对代谢和氧化损伤特别敏感。然而，这种敏感性的分子机制在体内尚未确定。PGC-1α（由 PPARGC1A 编码）以组织和细胞特异性的方式调节适应性代谢和氧化应激反应。异常的 PGC-1α 信号与神经退行性变有关，但它在中枢神经系统损伤中的作用机制尚不清楚。我们从一个小鼠模型中提供了证据，即 PGC-1α 的表达和活性在成年视网膜中被代谢和氧化应激所诱导。Ppargc1a 的缺失显著增加了 RGC 的丢失，与 PGC-1α 靶代谢和氧化应激反应基因的失调表达有关，包括 Hmox1（编码 HO-1）、Tfam 和 Vegfa。未经处理的和未处理的 Ppargc1a(-/-) 小鼠也表现出轻微的 RGC 丢失，以及出人意料的明显和一致的视网膜星形胶质细胞反应性。这些细胞在视网膜内层中对代谢稳态起着至关重要的调节作用。我们表明，PGC-1α 信号（以前在神经胶质细胞中未研究过）调节了星形胶质细胞对缺氧和氧化应激的解毒反应。最后，PGC-1α 的表达在内层视网膜中随年龄的增长而变化，并在慢性视神经病变模型中发生变化。这些数据表明 PGC-1α 信号作为一种重要的调节因子，调节星形胶质细胞反应性和 RGC 稳态，以协调对代谢和氧化损伤的致病易感性在视网膜内层。
