Institute of Stem Cell Research, Helmholtz Center Munich, 85764 Neuherberg, Germany.
Graduate School of Systemic Neuroscience, Biomedical Center, Faculty of Medicine, LMU Munich, 82152 Planegg, Germany.
Cells. 2020 Feb 3;9(2):350. doi: 10.3390/cells9020350.
Granulins (GRN) are secreted factors that promote neuronal survival and regulate inflammation in various pathological conditions. However, their roles in physiological conditions in the brain remain poorly understood. To address this knowledge gap, we analysed the telencephalon in Grn-deficient zebrafish and identified morphological and transcriptional changes in microglial cells, indicative of a pro-inflammatory phenotype in the absence of any insult. Unexpectedly, activated mutant microglia shared part of their transcriptional signature with aged human microglia. Furthermore, transcriptome profiles of the entire telencephali isolated from young Grn-deficient animals showed remarkable similarities with the profiles of the telencephali isolated from aged wildtype animals. Additionally, 50% of differentially regulated genes during aging were regulated in the telencephalon of young Grn-deficient animals compared to their wildtype littermates. Importantly, the telencephalon transcriptome in young Grn-deficent animals changed only mildly with aging, further suggesting premature aging of Grn-deficient brain. Indeed, Grn loss led to decreased neurogenesis and oligodendrogenesis, and to shortening of telomeres at young ages, to an extent comparable to that observed during aging. Altogether, our data demonstrate a role of Grn in regulating aging kinetics in the zebrafish telencephalon, thus providing a valuable tool for the development of new therapeutic approaches to treat age-associated pathologies.
颗粒蛋白（GRN）是一种分泌因子，可促进神经元存活并调节各种病理条件下的炎症。然而，它们在大脑生理条件下的作用仍知之甚少。为了解决这一知识空白，我们分析了 Grn 缺陷型斑马鱼的端脑，并发现小胶质细胞的形态和转录发生变化，表明在没有任何损伤的情况下存在促炎表型。出乎意料的是，激活的突变型小胶质细胞与衰老的人类小胶质细胞共享部分转录特征。此外，从小 Grn 缺陷型动物分离的整个端脑的转录组谱与从衰老野生型动物分离的端脑的转录组谱非常相似。此外，与年轻野生型同窝仔相比，在衰老过程中调节 50%差异表达基因的在年轻 Grn 缺陷型动物的端脑中被调节。重要的是，年轻 Grn 缺陷型动物端脑的转录组随年龄增长变化很小，这进一步表明 Grn 缺陷型大脑的过早衰老。事实上，Grn 的缺失导致神经发生和少突胶质细胞发生减少，端粒缩短，其程度与衰老过程中观察到的相当。总的来说，我们的数据表明 Grn 在调节斑马鱼端脑的衰老动力学中发挥作用，因此为开发治疗与年龄相关的病理的新治疗方法提供了有价值的工具。
