Department of Molecular Biology and Genetics, Weill Institute for Cell and Molecular Biology, Cornell University, 345 Weill Hall, Ithaca, NY, 14853, USA.
Acta Neuropathol. 2018 Jul;136(1):1-17. doi: 10.1007/s00401-018-1861-8. Epub 2018 May 9.
Progranulin (PGRN), encoded by the GRN gene in humans, is a secreted growth factor implicated in a multitude of processes ranging from regulation of inflammation to wound healing and tumorigenesis. The clinical importance of PGRN became especially evident in 2006, when heterozygous mutations in the GRN gene, resulting in haploinsufficiency, were found to be one of the main causes of frontotemporal lobar degeneration (FTLD). FTLD is a clinically heterogenous disease that results in the progressive atrophy of the frontal and temporal lobes of the brain. Despite significant research, the exact function of PGRN and its mechanistic relationship to FTLD remain unclear. However, growing evidence suggests a role for PGRN in the lysosome-most striking being that homozygous GRN mutation leads to neuronal ceroid lipofuscinosis, a lysosomal storage disease. Since this discovery, several links between PGRN and the lysosome have been established, including the existence of two independent lysosomal trafficking pathways, intralysosomal processing of PGRN into discrete functional peptides, and direct and indirect regulation of lysosomal hydrolases. Here, we summarize the cellular functions of PGRN, its roles in the nervous system, and its link to multiple neurodegenerative diseases, with a particular focus dedicated to recent lysosome-related mechanistic developments.
颗粒体蛋白聚糖 (PGRN) 由人类的 GRN 基因编码，是一种分泌型生长因子，涉及多种过程，从炎症调节到伤口愈合和肿瘤发生。PGRN 的临床重要性在 2006 年尤为明显，当时发现 GRN 基因的杂合突变导致单倍体不足，是额颞叶痴呆 (FTLD) 的主要原因之一。FTLD 是一种临床表现异质性的疾病，导致大脑额颞叶的进行性萎缩。尽管进行了大量研究，但 PGRN 的确切功能及其与 FTLD 的机制关系仍不清楚。然而，越来越多的证据表明 PGRN 在溶酶体中起作用，最明显的是 GRN 基因突变导致神经元蜡样脂褐质沉积症，一种溶酶体贮积病。自这一发现以来，已经确定了 PGRN 与溶酶体之间的几个联系，包括存在两种独立的溶酶体运输途径、PGRN 在溶酶体内加工成离散的功能肽，以及对溶酶体水解酶的直接和间接调节。在这里，我们总结了 PGRN 的细胞功能、它在神经系统中的作用及其与多种神经退行性疾病的联系，特别关注最近与溶酶体相关的机制发展。
