Department of Ophthalmology and Visual Sciences, University of Massachusetts Medical School, Worcester, MA 01655, USA.
Departments of Cell Biology and Ophthalmology and the Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
Biomolecules. 2021 Jun 11;11(6):871. doi: 10.3390/biom11060871.
Age-related macular degeneration (AMD) is a multifactorial disease of unclear etiology. We previously proposed that metabolic adaptations in photoreceptors (PRs) play a role in disease progression. We mimicked these metabolic adaptations in mouse PRs through deletion of the tuberous sclerosis complex (TSC) protein TSC1. Here, we confirm our previous findings by deletion of the other complex protein, namely TSC2, in rod photoreceptors. Similar to deletion of , mice with deletion of in rods develop AMD-like pathologies, including accumulation of apolipoproteins, migration of microglia, geographic atrophy, and neovascular pathologies. Subtle differences between the two mouse models, such as a significant increase in microglia activation with loss of , were seen as well. To investigate the role of altered glucose metabolism in disease pathogenesis, we generated mice with simulation deletions of and hexokinase-2 () in rods. Although retinal lactate levels returned to normal in mice with deletion, AMD-like pathologies still developed. The data suggest that the metabolic adaptations in PRs that cause AMD-like pathologies are independent of HK2-mediated aerobic glycolysis.
年龄相关性黄斑变性（AMD）是一种病因不明的多因素疾病。我们之前提出光感受器（PRs）中的代谢适应在疾病进展中起作用。我们通过敲除结节性硬化复合物（TSC）蛋白 TSC1 来模拟这些代谢适应。在这里，我们通过敲除另一种复合物蛋白 TSC2 在杆状光感受器中证实了我们之前的发现。与敲除 相似，敲除杆状细胞中的 会导致类似 AMD 的病理变化，包括载脂蛋白的积累、小胶质细胞的迁移、地理萎缩和新生血管病理。两种小鼠模型之间也存在细微差异，例如 缺失会导致小胶质细胞的激活显著增加。为了研究葡萄糖代谢改变在疾病发病机制中的作用，我们在杆状细胞中模拟敲除 和己糖激酶-2（）。尽管敲除 后视网膜中的乳酸水平恢复正常，但仍会出现类似 AMD 的病理变化。数据表明，导致类似 AMD 的病理变化的 PRs 代谢适应与 HK2 介导的有氧糖酵解无关。
