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.

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前颗粒蛋白：了解和治疗神经退行性疾病的新途径

前颗粒蛋白，一种分泌的糖蛋白，在人类中由单个GRN基因编码。前颗粒蛋白由十二个半胱氨酸颗粒蛋白基序的七个半连续重复的不同拷贝组成。许多细胞过程和疾病与这种独特的多效性因子有关，包括但不限于胚胎发生，肿瘤发生，炎症，伤口修复，神经变性和溶酶体功能。由GRN基因内的常染色体显性突变引起的单倍剂量不足会导致额颞叶变性，这是一种进行性神经元萎缩，在患者中表现为额颞痴呆。额颞痴呆是痴呆的一种早期发作形式，与阿尔茨海默氏病不同。该GRN额颞叶性痴呆的相关形式是一种蛋白病，其特征是出现了神经元内含物，该神经元内含物含有泛素化和片段化的TDP-43（由TARDBP编码）。最近已经报道了前颗粒蛋白的神经营养和神经免疫调节特性，但仍不为人所知。在阿尔茨海默氏病和帕金森氏病样疾病的实验模型中，GRN的基因传递抑制了表型的发展。在这里，我们回顾一下有关在体外和体内在正常生理和病理生理条件下前颗粒蛋白的分子功能和作用机理的已知知识楷模。着重介绍了颗粒蛋白原在治疗神经退行性疾病中的潜在治疗应用。