Ablation of pigment epithelium-derived factor receptor (PEDF-R/Pnpla2) causes photoreceptor degeneration.
Ablation of pigment epithelium-derived factor receptor (PEDF-R/Pnpla2) causes photoreceptor degeneration.
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DOI：
10.1016/j.jlr.2023.100358
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发表时间：
2023-05
影响因子：
6.5
通讯作者：
Becerra, S. Patricia
中科院分区：
文献类型：
--
作者：
Bernardo-Colon, Alexandra;Dong, Lijin;Abu-Asab, Mones;Brush, Richard S.;Agbaga, Martin -Paul;Becerra, S. Patricia
光感受器细胞表达编码色素上皮衍生因子受体（PEDF-R）（也称为ATGL）的马铃薯糖蛋白样磷脂酶结构域2（PNPLA 2）基因。PEDF-R表现出磷脂酶活性，介导其配体PEDF的神经营养作用。由于磷脂是视网膜中最丰富的脂质类，我们通过在无视网膜变性的背景下产生CRISPR Pnpla 2敲除小鼠系来研究PEDF-R在光感受器中的作用。Pnpla 2 −/−小鼠的视网膜Pnpla 2基因表达和PEDF-R蛋白水平分别通过RT-PCR和免疫荧光法检测。通过组织学和透射电子显微镜检查，PEDF-R缺陷的小鼠的光感受器具有畸形。Pnpla 2敲低降低了视网膜中PEDF-R的PLA 2酶活性。脂质组学分析揭示了溶血磷脂酰胆碱-DHA和溶血磷脂酰乙醇胺-DHA在PEDF-R缺陷视网膜中的积累，表明可能与感光功能障碍有因果关系。相对于对照组，PEDF-R的缺失降低了视紫红质、视蛋白、PKCα和突触素的水平。Pnpla 2 −/−光感受器表面暴露磷脂酰丝氨酸，其细胞核呈TUNEL阳性并浓缩，表明细胞凋亡开始。PEDF-R缺陷除了其结构缺陷外，还损害了体内感光细胞功能，如通过视网膜电图测定的Pnpla 2 −/−和Pnpla 2 +/−小鼠相对于对照组的感光细胞a波和b波衰减所示。总之，在小鼠中消融PEDF-R引起与光感受器的畸形和性能不良相关的磷脂组成的改变。这些发现将PEDF-R鉴定为感光器结构和功能的重要组分，突出了其在视网膜存活及其后果的磷脂代谢中的作用。
Photoreceptor cells express the patatin-like phospholipase domain-containing 2 (PNPLA2) gene that codes for pigment epithelium-derived factor receptor (PEDF-R) (also known as ATGL). PEDF-R exhibits phospholipase activity that mediates the neurotrophic action of its ligand PEDF. Because phospholipids are the most abundant lipid class in the retina, we investigated the role of PEDF-R in photoreceptors by generating CRISPR Pnpla2 knock-out mouse lines in a retinal degeneration-free background. Pnpla2−/− mice had undetectable retinal Pnpla2 gene expression and PEDF-R protein levels as assayed by RT-PCR and immunofluorescence, respectively. The photoreceptors of mice deficient in PEDF-R had deformities as examined by histology and transmission electron microscopy. Pnpla2 knockdown diminished the PLA2 enzymatic activity of PEDF-R in the retina. Lipidomic analyses revealed the accumulation of lysophosphatidyl choline-DHA and lysophosphatidyl ethanolamine-DHA in PEDF-R-deficient retinas, suggesting a possible causal link to photoreceptor dysfunction. Loss of PEDF-R decreased levels of rhodopsin, opsin, PKCα, and synaptophysin relative to controls. Pnpla2−/− photoreceptors had surface-exposed phosphatidylserine, and their nuclei were TUNEL positive and condensed, revealing an apoptotic onset. Paralleling its structural defects, PEDF-R deficiency compromised photoreceptor function in vivo as indicated by the attenuation of photoreceptor a- and b-waves in Pnpla2−/− and Pnpla2+/− mice relative to controls as determined by electroretinography. In conclusion, ablation of PEDF-R in mice caused alteration in phospholipid composition associated with malformation and malperformance of photoreceptors. These findings identify PEDF-R as an important component for photoreceptor structure and function, highlighting its role in phospholipid metabolism for retinal survival and its consequences.
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