Mass Spectrometry Research Center and Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN, USA.
Department of Ophthalmology, Storm Eye Institute, Medical University of South Carolina, Charleston, SC, USA.
Sci Rep. 2017 Dec 11;7(1):17352. doi: 10.1038/s41598-017-17402-1.
Stargardt disease is a juvenile onset retinal degeneration, associated with elevated levels of lipofuscin and its bis-retinoid components, such as N-retinylidene-N-retinylethanolamine (A2E). However, the pathogenesis of Stargardt is still poorly understood and targeted treatments are not available. Utilizing high spatial and high mass resolution matrix assisted laser desorption ionization (MALDI) imaging mass spectrometry (IMS), we determined alterations of lipid profiles specifically localized to the retinal pigment epithelium (RPE) in Abca4 Stargardt model mice compared to their relevant background strain. Extensive analysis by LC-MS/MS in both positive and negative ion mode was required to accurately confirm the identity of one highly expressed lipid class, bis(monoacylgylercoro)phosphate (BMP) lipids, and to distinguish them from isobaric species. The same BMP lipids were also detected in the RPE of healthy human retina. BMP lipids have been previously associated with the endosomal/lysosomal storage diseases Niemann-Pick and neuronal ceroid lipofuscinosis and have been reported to regulate cholesterol levels in endosomes. These results suggest that perturbations in lipid metabolism associated with late endosomal/lysosomal dysfunction may play a role in the pathogenesis of Stargardt disease and is evidenced in human retinas.
斯塔加特病是一种青少年发病的视网膜退行性疾病，与脂褐素及其双视黄醇成分（如 N-视黄基-N-视黄基乙醇胺（A2E））水平升高有关。然而，斯塔加特病的发病机制仍不清楚，也没有针对性的治疗方法。利用高空间分辨率和高质量分辨率的基质辅助激光解吸电离（MALDI）成像质谱（IMS），我们确定了 Abca4 斯塔加特模型小鼠的视网膜色素上皮（RPE）中脂质谱的改变，与它们相关的背景品系相比。需要通过正离子和负离子模式的 LC-MS/MS 进行广泛分析，以准确确认一个高度表达的脂质类别的身份，即双（单酰甘油）磷酸酯（BMP）脂质，并将其与等质异位体区分开来。在健康人视网膜的 RPE 中也检测到了相同的 BMP 脂质。BMP 脂质以前与溶酶体贮积病尼曼-皮克病和神经元蜡样脂褐质沉积症有关，并且据报道它们可以调节内体中的胆固醇水平。这些结果表明，与晚期内体/溶酶体功能障碍相关的脂质代谢紊乱可能在斯塔加特病的发病机制中起作用，并在人视网膜中得到证实。
