Pohl Sandra, Mitchison Hannah M, Kohlschütter Alfried, van Diggelen Otto, Braulke Thomas, Storch Stephan
Department of Biochemistry, Children's Hospital, University Medical Center Hamburg, Hamburg, Germany.
J Neurochem. 2007 Dec;103(6):2177-88. doi: 10.1111/j.1471-4159.2007.04920.x. Epub 2007 Sep 11.
Juvenile neuronal ceroid lipofuscinosis (Batten disease) is a neurodegenerative disorder caused by defective function of the lysosomal membrane glycoprotein CLN3. The activity of the lysosomal acid phosphatase (LAP/ACP2) was found to be significantly increased in the cerebellum and brain stem of Cln3-targeted mice during the early stages of postnatal life. Histochemical localization studies revealed an increased LAP/ACP2 staining intensity in neurons of the cerebral cortex of 48-week-old Cln3-targeted mice as compared with controls. Additionally, the expression of another lysosomal membrane protein LAMP-2 was increased in all brain areas. Knockdown of CLN3 expression in HeLa cells by RNA interference also resulted in increased LAP/ACP2 and LAMP-2 expression. Finally in fibroblasts of two juvenile neuronal ceroid lipofuscinosis patients elevated levels of LAP/ACP2 were found. Both activation of gene transcription and increased protein half-life appear to contribute to increased LAP/ACP2 protein expression in CLN3-deficient cells. The data suggest that lysosomal dysfunction and accumulation of storage material require increased biogenesis of LAP/ACP2 and LAMP-2 positive membranes which makes LAP/ACP2 suitable as biomarker of Batten disease.
青少年神经元蜡样脂褐质沉积症（巴顿病）是一种由溶酶体膜糖蛋白CLN3功能缺陷引起的神经退行性疾病。在出生后早期，靶向Cln3的小鼠小脑和脑干中溶酶体酸性磷酸酶（LAP/ACP2）的活性显著增加。组织化学定位研究显示，与对照组相比，48周龄靶向Cln3的小鼠大脑皮质神经元中LAP/ACP2染色强度增加。此外，另一种溶酶体膜蛋白LAMP-2在所有脑区的表达均增加。通过RNA干扰敲低HeLa细胞中CLN3的表达也导致LAP/ACP2和LAMP-2表达增加。最后，在两名青少年神经元蜡样脂褐质沉积症患者的成纤维细胞中发现LAP/ACP2水平升高。基因转录激活和蛋白质半衰期延长似乎都导致CLN3缺陷细胞中LAP/ACP2蛋白表达增加。数据表明，溶酶体功能障碍和储存物质的积累需要增加LAP/ACP2和LAMP-2阳性膜的生物合成，这使得LAP/ACP2适合作为巴顿病的生物标志物。
