A Mutation in Transmembrane Protein 135 Impairs Lipid Metabolism in Mouse Eyecups

Aging is a significant factor in the development of age-related diseases but the molecular underpinnings of how aging disrupts cellular homeostasis to cause retinal disease is unknown. Here, we further our studies on Transmembrane protein 135 (Tmem135), a gene involved in retinal aging, by examining the transcriptomic profiles of wildtype, heterozygous and homozygous Tmem135 mutant posterior eyecup samples through RNA sequencing (RNA-Seq). We found significant gene expression changes in both heterozygous and homozygous Tmem135 mutant mouse eyecups that correlates with visual function deficits. Further analysis revealed many genes involved in lipid metabolism are changed due to the Tmem135 mutation. We confirm these changes by finding increased lipid accumulation in mutant Tmem135 eyecup samples. Since mutant Tmem135 mice have similar ocular pathologies as human age-related macular degeneration (AMD) eyes, we compared our homozygous Tmem135 mutant eyecup RNA-Seq dataset with datasets of human AMD donor eyes. We find similar changes in genes involved in lipid metabolism between the homozygous Tmem135 mutant eyecups and AMD donor eyes. Our study suggests that the Tmem135 mutation affects lipid metabolism as similarly observed in human AMD eyes, thus Tmem135 mutant mice can serve as a good model for the role of dysregulated lipid metabolism in AMD. mRNA profiles of WT, Tmem135FUN025/+, and Tmem135FUN025/FUN025 posterior eye cups without the neural retina衰老是年龄相关性疾病发生发展的关键影响因素，但衰老如何破坏细胞稳态并引发视网膜疾病的分子基础仍未阐明。本研究针对参与视网膜衰老的跨膜蛋白135（Transmembrane protein 135, Tmem135）展开进一步研究，通过RNA测序（RNA-Seq）分析野生型、杂合型及纯合型Tmem135突变小鼠去除神经视网膜的后眼杯样本的转录组谱。研究发现，杂合型与纯合型Tmem135突变小鼠的眼杯样本均存在显著的基因表达改变，且该改变与视觉功能缺陷存在相关性。进一步分析显示，Tmem135突变会导致大量脂代谢相关基因的表达发生变化；我们通过检测到Tmem135突变小鼠眼杯样本中脂质蓄积增加的现象，验证了上述基因表达变化。鉴于Tmem135突变小鼠的眼部病理特征与人类年龄相关性黄斑变性（age-related macular degeneration, AMD）患者的眼部病变相似，我们将纯合型Tmem135突变小鼠眼杯的RNA测序数据集与人类AMD供体眼的转录组数据集进行了比对分析，结果发现二者脂代谢相关基因的表达变化模式高度一致。本研究表明，Tmem135突变可影响脂代谢过程，这一现象与人类AMD患者眼部的改变高度相似，因此Tmem135突变小鼠可作为研究脂代谢失调在AMD发病机制中作用的优良动物模型。本数据集包含野生型（WT）、Tmem135^FUN025/+杂合型及Tmem135^FUN025/FUN025纯合型小鼠去除神经视网膜的后眼杯的mRNA转录谱。