Molecular Pharmacology, Department of Biofunctional Evaluation, Gifu Pharmaceutical University, Gifu, Japan.
Molecular Pharmacology, Department of Biofunctional Evaluation, Gifu Pharmaceutical University, Gifu, Japan
In Vivo. 2022 Mar-Apr;36(2):610-617. doi: 10.21873/invivo.12744.
Homozygous loss-of-function progranulin gene (GRN) mutation carriers develop adult-onset neuronal ceroid lipofuscinosis (NCL), a lysosomal storage disease. Clinically, NCL patients display retinal degeneration and visual dysfunction. However, there is little information about the effects of progranulin dysfunction on lysosomal function of the retinal pigment epithelium (RPE).
We performed RNA interference knock down of progranulin in primary human RPE (hRPE) cells and observed RPE function and lysosomal activity.
Progranulin localized to the lysosome in RPE cells. Loss of progranulin did not affect the biogenesis of lysosomes in RPE cells, while it was necessary for the activation of lysosomal proteases. Furthermore, progranulin deficiency decreased cell viability and disrupted the cell-cell junctions.
Our results demonstrate that progranulin insufficiency disturbs lysosomal activity and physiological functions in RPE cells.
同源性缺失功能的颗粒蛋白前体基因（GRN）突变携带者会患上成年发病的神经元蜡样脂褐质沉积症（NCL），这是一种溶酶体贮积症。临床上，NCL 患者会出现视网膜变性和视觉功能障碍。然而，关于颗粒蛋白功能障碍对视网膜色素上皮（RPE）溶酶体功能的影响，目前信息较少。
我们在原代人 RPE（hRPE）细胞中进行颗粒蛋白前体基因的 RNA 干扰敲低，并观察 RPE 功能和溶酶体活性。
颗粒蛋白在 RPE 细胞的溶酶体中定位。RPE 细胞中颗粒蛋白的缺失并不影响溶酶体的生物发生，但对于溶酶体蛋白酶的激活是必需的。此外，颗粒蛋白缺乏会降低细胞活力并破坏细胞间连接。
我们的结果表明，颗粒蛋白不足会扰乱 RPE 细胞中的溶酶体活性和生理功能。
