Progranulin Deficiency Promotes Circuit-Specific Synaptic Pruning by Microglia via Complement Activation.
Progranulin Deficiency Promotes Circuit-Specific Synaptic Pruning by Microglia via Complement Activation.
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DOI：
10.1016/j.cell.2016.04.001
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发表时间：
2016-05-05
期刊：
影响因子：
64.5
通讯作者：
Huang EJ
中科院分区：
文献类型：
--
作者：
Lui H;Zhang J;Makinson SR;Cahill MK;Kelley KW;Huang HY;Shang Y;Oldham MC;Martens LH;Gao F;Coppola G;Sloan SA;Hsieh CL;Kim CC;Bigio EH;Weintraub S;Mesulam MM;Rademakers R;Mackenzie IR;Seeley WW;Karydas A;Miller BL;Borroni B;Ghidoni R;Farese RV Jr;Paz JT;Barres BA;Huang EJ
小胶质细胞在大脑中维持稳态，但异常的小胶质细胞激活是否会导致神经退行性变仍然存在争议。在这里，我们使用转录组分析来证明额颞叶痴呆（FTD）基因前颗粒蛋白（Grn）的缺乏导致溶酶体和先天免疫基因的年龄依赖性、进行性上调、补体产生增加和小胶质细胞突触修剪增强。在衰老过程中，Grn−/−小鼠表现出深度的小胶质细胞浸润和丘脑腹侧抑制性突触的优先消除，这导致丘脑皮质回路的高兴奋性和强迫症（OCD）样梳理行为。值得注意的是，删除C1qa基因可显著减少Grn - / -小胶质细胞的突触修剪，并减轻Grn - / -小鼠的神经变性、行为表型和过早死亡。总之，我们的研究结果揭示了前颗粒蛋白在抑制衰老过程中异常小胶质细胞激活中的先前未被认识到的作用。这些结果代表了补体激活和小胶质细胞介导的突触修剪是由前颗粒蛋白缺乏引起的神经变性的主要驱动因素，而不是后果的重要概念进展。
Microglia maintain homeostasis in the brain, but whether aberrant microglial activation can cause neurodegeneration remains controversial. Here, we use transcriptome profiling to demonstrate that deficiency in frontotemporal dementia (FTD) gene progranulin (Grn) leads to an age-dependent, progressive up-regulation of lysosomal and innate immunity genes, increased complement production, and enhanced synaptic pruning in microglia. During aging, Grn−/− mice show profound microglia infiltration and preferential elimination of inhibitory synapses in the ventral thalamus, which lead to hyperexcitability in the thalamocortical circuits and obsessive-compulsive disorder (OCD)-like grooming behaviors. Remarkably, deleting C1qa gene significantly reduces synaptic pruning by Grn−/− microglia, and mitigates neurodegeneration, behavioral phenotypes and premature mortality in Grn−/− mice. Together, our results uncover a previously unrecognized role of progranulin in suppressing aberrant microglia activation during aging. These results represent an important conceptual advance that complement activation and microglia-mediated synaptic pruning are major drivers, rather than consequences, of neurodegeneration caused by progranulin deficiency.