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首页> 外文期刊>BMC Neuroscience >Progranulin is expressed within motor neurons and promotes neuronal cell survival
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Progranulin is expressed within motor neurons and promotes neuronal cell survival

机译：前颗粒蛋白在运动神经元内表达并促进神经元细胞存活

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Background Progranulin is a secreted high molecular weight growth factor bearing seven and one half copies of the cysteine-rich granulin-epithelin motif. While inappropriate over-expression of the progranulin gene has been associated with many cancers, haploinsufficiency leads to atrophy of the frontotemporal lobes and development of a form of dementia (frontotemporal lobar degeneration with ubiquitin positive inclusions, FTLD-U) associated with the formation of ubiquitinated inclusions. Recent reports indicate that progranulin has neurotrophic effects, which, if confirmed would make progranulin the only neuroprotective growth factor that has been associated genetically with a neurological disease in humans. Preliminary studies indicated high progranulin gene expression in spinal cord motor neurons. However, it is uncertain what the role of Progranulin is in normal or diseased motor neuron function. We have investigated progranulin gene expression and subcellular localization in cultured mouse embryonic motor neurons and examined the effect of progranulin over-expression and knockdown in the NSC-34 immortalized motor neuron cell line upon proliferation and survival. Results In situ hybridisation and immunohistochemical techniques revealed that the progranulin gene is highly expressed by motor neurons within the mouse spinal cord and in primary cultures of dissociated mouse embryonic spinal cord-dorsal root ganglia. Confocal microscopy coupled to immunocytochemistry together with the use of a progranulin-green fluorescent protein fusion construct revealed progranulin to be located within compartments of the secretory pathway including the Golgi apparatus. Stable transfection of the human progranulin gene into the NSC-34 motor neuron cell line stimulates the appearance of dendritic structures and provides sufficient trophic stimulus to survive serum deprivation for long periods (up to two months). This is mediated at least in part through an anti-apoptotic mechanism. Control cells, while expressing basal levels of progranulin do not survive in serum free conditions. Knockdown of progranulin expression using shRNA technology further reduced cell survival. Conclusion Neurons are among the most long-lived cells in the body and are subject to low levels of toxic challenges throughout life. We have demonstrated that progranulin is abundantly expressed in motor neurons and is cytoprotective over prolonged periods when over-expressed in a neuronal cell line. This work highlights the importance of progranulin as neuroprotective growth factor and may represent a therapeutic target for neurodegenerative diseases including motor neuron disease.
机译：背景颗粒蛋白原是一种分泌的高分子量生长因子，带有七个半拷贝的富含半胱氨酸的颗粒蛋白上皮素基序。虽然前颗粒蛋白基因的不适当过度表达与许多癌症有关，但单倍剂量不足会导致额颞叶萎缩并发展为痴呆症（额颞叶变性并伴有泛素阳性包涵体，FTLD-U）与遍在蛋白化的形成有关夹杂物。最近的报道表明，颗粒蛋白原具有神经营养作用，如果证实，它将使颗粒蛋白原成为与人类神经系统疾病遗传相关的唯一神经保护性生长因子。初步研究表明，脊髓运动神经元中progranulin基因表达高。但是，尚不确定前颗粒蛋白在正常或患病的运动神经元功能中的作用。我们研究了原粒蛋白基因表达和培养的小鼠胚胎运动神经元中的亚细胞定位，并研究了原粒蛋白过表达和NSC-34永生化运动神经元细胞系对增殖和存活的抑制作用。结果原位杂交和免疫组织化学技术表明，前颗粒蛋白基因在小鼠脊髓内和分离的小鼠胚胎脊髓-背根神经节的原代培养物中由运动神经元高度表达。共聚焦显微镜结合免疫细胞化学，并使用前颗粒蛋白-绿色荧光蛋白融合构建体，发现前颗粒蛋白位于包括高尔基体在内的分泌途径的各个部分。将人类前颗粒蛋白基因稳定转染到NSC-34运动神经元细胞系中可刺激树突状结构的出现，并提供足够的营养刺激，使其在血清缺乏的情况下能够长期存活（长达两个月）。这至少部分地通过抗凋亡机制介导。对照细胞虽然表达基础水平的颗粒蛋白原，但在无血清条件下无法存活。使用shRNA技术抑制原粒蛋白表达进一步降低了细胞存活率。结论神经元是人体中寿命最长的细胞之一，并且一生中都受到低水平的毒性挑战。我们已经证明，前颗粒蛋白在运动神经元中大量表达，并且当在神经元细胞系中过表达时，在长时间内具有细胞保护作用。这项工作强调了颗粒蛋白原作为神经保护性生长因子的重要性，并可能代表包括神经运动疾病在内的神经退行性疾病的治疗目标。

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