Dissociation of frontotemporal dementia-related deficits and neuroinflammation in progranulin haploinsufficient mice.
Dissociation of frontotemporal dementia-related deficits and neuroinflammation in progranulin haploinsufficient mice.
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DOI：
10.1523/jneurosci.6103-11.2013
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发表时间：
2013-03-20
期刊：
影响因子：
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通讯作者：
Roberson ED
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作者：
Filiano AJ;Martens LH;Young AH;Warmus BA;Zhou P;Diaz-Ramirez G;Jiao J;Zhang Z;Huang EJ;Gao FB;Farese RV Jr;Roberson ED
额颞叶痴呆（FTD）是一种神经退行性疾病，具有社会和情感功能缺陷的标志。GRN（颗粒蛋白前体基因）的杂合性功能丧失突变是该疾病的常见遗传原因，但颗粒蛋白前体单倍不足导致FTD神经元功能障碍的机制尚不清楚。纯合颗粒蛋白前体基因敲除（Grn−/−）小鼠已被研究作为这种疾病的模型，并显示出行为缺陷和神经炎性表型，具有强大的小胶质细胞活化。然而，纯合GRN突变导致完全颗粒蛋白前体缺乏症最近被证明会导致不同的神经系统疾病，神经元蜡样质脂褐质沉积症，这表明完全缺乏颗粒蛋白前体可能具有不同于单倍不足的影响。在这里，我们研究了颗粒蛋白前体杂合（Grn+/−）小鼠，其模型颗粒蛋白前体单倍不足。我们发现Grn+/−小鼠出现了与FTD潜在相关的年龄依赖性社交和情感缺陷。然而，与Grn−/−小鼠不同，Grn+/−小鼠的行为缺陷发生在没有神经胶质增生或肿瘤坏死因子-α表达增加的情况下。相反，我们在Grn+/−小鼠中发现了杏仁核（FTD的一个选择性脆弱区域）的神经元异常。我们的研究结果表明，FTD相关的缺陷，由于颗粒蛋白原单倍不足，可以在没有可检测到的胶质细胞增生和神经炎症，从而解离小胶质细胞激活功能缺陷，并提出了一个重要的影响颗粒蛋白原缺乏神经元。
Frontotemporal dementia (FTD) is a neurodegenerative disease with hallmark deficits in social and emotional function. Heterozygous loss-of-function mutations in GRN, the progranulin gene, are a common genetic cause of the disorder, but the mechanisms by which progranulin haploinsufficiency causes neuronal dysfunction in FTD are unclear. Homozygous progranulin knockout (Grn−/−) mice have been studied as a model of this disorder and show behavioral deficits and a neuroinflammatory phenotype with robust microglial activation. However, homozygous GRN mutations causing complete progranulin deficiency were recently shown to cause a different neurological disorder, neuronal ceroid lipofuscinosis, suggesting that the total absence of progranulin may have effects distinct from those of haploinsufficiency. Here, we studied progranulin heterozygous (Grn+/−) mice, which model progranulin haploinsufficiency. We found that Grn+/− mice developed age-dependent social and emotional deficits potentially relevant to FTD. However, unlike Grn−/− mice, behavioral deficits in Grn+/− mice occurred in the absence of gliosis or increased expression of tumor necrosis factor–α. Instead, we found neuronal abnormalities in the amygdala, an area of selective vulnerability in FTD, in Grn+/− mice. Our findings indicate that FTD-related deficits due to progranulin haploinsufficiency can develop in the absence of detectable gliosis and neuroinflammation, thereby dissociating microglial activation from functional deficits and suggesting an important effect of progranulin deficiency on neurons.