Progranulin deficiency promotes neuroinflammation and neuron loss following toxin-induced injury
Progranulin deficiency promotes neuroinflammation and neuron loss following toxin-induced injury
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DOI：
10.1172/jci63113
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发表时间：
2012-11-01
影响因子：
15.9
通讯作者：
Farese, Robert V., Jr.
中科院分区：
文献类型：
--
作者：
Martens, Lauren Henl;Zhang, Jiasheng;Farese, Robert V., Jr.
颗粒蛋白原（PGRN）是一种广泛表达的分泌蛋白，与炎症有关。在人类中，PGRN单倍不足是额颞叶痴呆（FTD）的主要遗传原因，但PGRN缺乏如何导致神经变性尚不清楚。在这里，我们表明，PGRN的损失增加的神经元损失在中枢神经系统损伤的结果。当急性暴露于1-甲基-4-（2 '-甲基苯基）-1，2，3，6-四氢嘧啶（MPTP）时，与野生型小鼠相比，缺乏PGRN的小鼠（Grn（-/-））显示出更多的神经元损失和增加的小胶质细胞增生。加重的神经元损失不是由于Grn（-/-）神经元对MPTP的选择性脆弱性，而是由于增加的小胶质细胞炎症反应。与此一致，在小胶质细胞中缺乏PGRN的条件突变体表现出与Grn（-/-）小鼠相似的MPTP诱导的表型。在混合皮质培养物中，选择性耗尽来自小胶质细胞的PGRN导致在没有损伤的情况下野生型神经元的死亡增加。此外，用LPS/IFN-γ处理的Grn（-/-）小胶质细胞表现出放大的炎症反应，并且来自这些小胶质细胞的条件培养基促进培养的神经元的死亡。我们的研究结果表明，PGRN缺乏导致失调的小胶质细胞激活，从而有助于增加神经元损失与损伤。这些发现表明，PGRN缺乏可能导致其他形式的CNS损伤伴神经炎症的神经元损失增加。
Progranulin (PGRN) is a widely expressed secreted protein that is linked to inflammation. In humans, PGRN haploinsufficiency is a major inherited cause of frontotemporal dementia (FTD), but how PGRN deficiency causes neurodegeneration is unknown. Here we show that loss of PGRN results in increased neuron loss in response to injury in the CNS. When exposed acutely to 1-methyl-4-(2'-methylphenyl)-1,2,3,6-tetrahydrophine (MPTP), mice lacking PGRN (Grn(-/-)) showed more neuron loss and increased microgliosis compared with wild-type mice. The exacerbated neuron loss was due not to selective vulnerability of Grn(-/-) neurons to MPTP, but rather to an increased microglial inflammatory response. Consistent with this, conditional mutants lacking PGRN in microglia exhibited MPTP-induced phenotypes similar to Grn(-/-) mice. Selective depletion of PGRN from microglia in mixed cortical cultures resulted in increased death of wild-type neurons in the absence of injury. Furthermore, Grn(-/-) microglia treated with LPS/IFN-gamma exhibited an amplified inflammatory response, and conditioned media from these microglia promoted death of cultured neurons. Our results indicate that PGRN deficiency leads to dysregulated microglial activation and thereby contributes to increased neuron loss with injury. These findings suggest that PGRN deficiency may cause increased neuron loss in other forms of CNS injury accompanied by neuroinflammation.