Endocrine Research Laboratory, Royal Victoria Hospital, and McGill University Health Centre Research Institute, Centre for Translational Biology, Platform in Metabolic Disorders and Complications, 1001 Decarie Boulevard, QC, Canada, H4A 3J1.
Brain. 2017 Dec 1;140(12):3081-3104. doi: 10.1093/brain/awx198.
Progranulin, a secreted glycoprotein, is encoded in humans by the single GRN gene. Progranulin consists of seven and a half, tandemly repeated, non-identical copies of the 12 cysteine granulin motif. Many cellular processes and diseases are associated with this unique pleiotropic factor that include, but are not limited to, embryogenesis, tumorigenesis, inflammation, wound repair, neurodegeneration and lysosome function. Haploinsufficiency caused by autosomal dominant mutations within the GRN gene leads to frontotemporal lobar degeneration, a progressive neuronal atrophy that presents in patients as frontotemporal dementia. Frontotemporal dementia is an early onset form of dementia, distinct from Alzheimer's disease. The GRN-related form of frontotemporal lobar dementia is a proteinopathy characterized by the appearance of neuronal inclusions containing ubiquitinated and fragmented TDP-43 (encoded by TARDBP). The neurotrophic and neuro-immunomodulatory properties of progranulin have recently been reported but are still not well understood. Gene delivery of GRN in experimental models of Alzheimer's- and Parkinson's-like diseases inhibits phenotype progression. Here we review what is currently known concerning the molecular function and mechanism of action of progranulin in normal physiological and pathophysiological conditions in both in vitro and in vivo models. The potential therapeutic applications of progranulin in treating neurodegenerative diseases are highlighted.
颗粒蛋白前体（Progranulin）是一种分泌型糖蛋白，由人类单个 GRN 基因编码。颗粒蛋白前体由七个半串联重复的、非同源的 12 个半胱氨酸颗粒素基序组成。许多细胞过程和疾病都与这种独特的多功能因子有关，包括但不限于胚胎发生、肿瘤发生、炎症、伤口修复、神经退行性变和溶酶体功能。GRN 基因的常染色体显性突变导致的单倍不足会导致额颞叶痴呆，这是一种进行性神经元萎缩的疾病，在患者中表现为额颞叶痴呆。额颞叶痴呆是一种早发性痴呆，与阿尔茨海默病不同。GRN 相关的额颞叶痴呆是一种蛋白病，其特征是神经元内含物的出现，这些内含物含有泛素化和碎片化的 TDP-43（由 TARDBP 编码）。颗粒蛋白前体的神经营养和神经免疫调节特性最近被报道，但仍不被完全理解。在阿尔茨海默病和帕金森病样疾病的实验模型中，GRN 的基因传递抑制了表型的进展。在这里，我们回顾了目前已知的颗粒蛋白前体在体外和体内模型中正常生理和病理生理条件下的分子功能和作用机制。强调了颗粒蛋白前体在治疗神经退行性疾病方面的潜在治疗应用。
