Progranulin deficiency leads to reduced glucocerebrosidase activity

Mutation in the GRN gene, encoding the progranulin (PGRN) protein, shows a dose-dependent disease correlation, wherein haploinsufficiency results in frontotemporal lobar degeneration (FTLD) and complete loss results in neuronal ceroid lipofuscinosis (NCL). Although the exact function of PGRN is unknown, it has been increasingly implicated in lysosomal physiology. Here we report that PGRN interacts with the lysosomal enzyme, glucocerebrosidase (GCase), and is essential for proper GCase activity. GCase activity is significantly reduced in tissue lysates from PGRN-deficient mice. This is further evidence that reduced lysosomal hydrolase activity may be a pathological mechanism in cases of GRN-related FTLD and NCL.编码颗粒蛋白前体（progranulin, PGRN）的GRN基因（GRN gene）发生突变，呈现剂量依赖性的疾病关联：其中单倍体剂量不足（haploinsufficiency）可引发额颞叶变性（frontotemporal lobar degeneration, FTLD），而基因完全缺失则导致神经元蜡样脂褐质沉积症（neuronal ceroid lipofuscinosis, NCL）。尽管PGRN的确切功能尚未阐明，但越来越多的研究表明其参与溶酶体生理（lysosomal physiology）过程。本研究证实，PGRN可与溶酶体酶葡糖脑苷脂酶（glucocerebrosidase, GCase）相互作用，且对维持GCase的正常活性至关重要。在PGRN缺陷小鼠的组织裂解物中，GCase活性显著降低。这进一步表明，溶酶体水解酶活性降低或许是GRN相关FTLD与NCL的病理机制之一。