Progranulin Deficiency Promotes Circuit-Specific Synaptic Pruning by Microglia via Complement Activation

Microglia repair injury and maintain homeostasis in the brain, but whether aberrant microglial activation can contribute to neurodegeneration remains unclear. 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 synaptic pruning activity in microglia. During aging, Grn-/- mice show profound accumulation of microglia and preferential elimination of inhibitory synapses in the ventral thalamus, which contribute to hyperexcitability in the thalamocortical circuits and obsessive-compulsive disorder (OCD)-like grooming behaviors. Remarkably, blocking complement activation by deleting C1qa gene significantly reduces synaptic pruning by Grn-/- microglia, and mitigates neurodegeneration, behavioral phenotypes and premature mortality in Grn-/- mice. These results uncover a previously unrecognized role of progranulin in suppressing microglia activation during aging, and support the idea that blocking complement activation is a promising therapeutic target for neurodegeneration caused by progranulin deficiency. Gene expression study in multiple brain regions from a mouse model of progranulin deficiency Please note that 9 outlier samples were excluded from data analysis. Therefore, there are 326 raw data columns (i.e. 163 samples) in the non_normalized data matrix while 154 samples are represented here.小胶质细胞（Microglia）能够修复大脑损伤并维持脑内稳态，但异常激活的小胶质细胞是否会参与神经退行性病变的发生发展，目前仍未明确。本研究通过转录组谱分析证实，额颞叶痴呆（FTD）致病基因前颗粒蛋白（Grn）的缺失，会导致小鼠呈现年龄依赖性的渐进性溶酶体与先天免疫相关基因上调表达，补体生成增加，且小胶质细胞的突触修剪活性增强。在衰老进程中，Grn基因敲除（Grn-/-）小鼠的腹侧丘脑内会出现小胶质细胞的显著聚集，并优先清除抑制性突触，这会引发丘脑皮层回路过度兴奋以及类强迫症（OCD）样理毛行为。值得注意的是，通过敲除C1qa基因阻断补体激活，可显著降低Grn-/-小胶质细胞的突触修剪能力，并缓解Grn-/-小鼠的神经退行性病变、行为表型异常与过早死亡。上述研究结果揭示了前颗粒蛋白在衰老过程中抑制小胶质细胞激活的此前未被认知的作用，并支持补体激活阻断疗法可作为前颗粒蛋白缺失所致神经退行性病变的极具潜力的治疗靶点这一观点。本研究从前颗粒蛋白缺失小鼠模型的多个脑区采集样本开展基因表达研究。请注意，共有9个异常样本被排除在数据分析之外。因此，非标准化数据矩阵中共包含326个原始数据列（即163个样本），而本次公开的数据中共包含154个样本。