Cell-autonomous immune dysfunction driven by disrupted autophagy in C9orf72 -ALS iPSC-derived microglia contributes to neurodegeneration
Cell-autonomous immune dysfunction driven by disrupted autophagy in C9orf72 -ALS iPSC-derived microglia contributes to neurodegeneration
复制标题
C9orf72 -ALS iPSC 衍生小胶质细胞中自噬破坏驱动的细胞自主免疫功能障碍导致神经退行性变
DOI：
10.1101/2022.05.12.491675
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发表时间：
2022
期刊：
影响因子：
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通讯作者：
Banerjee P
中科院分区：
文献类型：
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作者：
Banerjee P
虽然小胶质细胞的激活在肌萎缩侧索硬化症(ALS)和额颞部痴呆(FTD)中被广泛发现，但其潜在的机制(S)却鲜为人知。在这里，我们使用具有最常见的ALS/FTD突变(C9orf72，mC9-MG)、基因校正的同基因对照(isC9-MG)和C9orf72基因敲除的HiPSC-MG(C9KO-MG)的人诱导多能干细胞衍生小胶质细胞样细胞(hiPSC-MG)，我们发现C9ORF72蛋白减少与吞噬功能受损和内毒素刺激下的免疫反应增强有关。对C9ORF72相互作用组的分析表明，C9ORF72与自噬调节因子相互作用，功能研究表明，在mC9-MG和C9KO-MG中，自噬的启动受到抑制。与运动神经元的共培养研究表明，mC9-MG的自噬缺陷增加了mC9-MNS对兴奋毒性刺激的易感性。自噬的药理激活改善了HiPSC-MG的细胞自主功能缺陷和MG-MN共培养中的MN死亡。综上所述，这些发现揭示了C9ORF72在调节免疫动态平衡中的重要作用，并发现髓系细胞的调节失调是ALS/FTD神经退行性变的一个因素。
Although microglial activation is widely found in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), the underlying mechanism(s) are poorly understood. Here, using human-induced pluripotent stem cell–derived microglia-like cells (hiPSC-MG) harboring the most common ALS/FTD mutation (C9orf72, mC9-MG), gene-corrected isogenic controls (isoC9-MG), andC9orf72knockout hiPSC-MG (C9KO-MG), we show that reduced C9ORF72 protein is associated with impaired phagocytosis and an exaggerated immune response upon stimulation with lipopolysaccharide. Analysis of the C9ORF72 interactome revealed that C9ORF72 interacts with regulators of autophagy and functional studies showed impaired initiation of autophagy in mC9-MG and C9KO-MG. Coculture studies with motor neurons (MNs) demonstrated that the autophagy deficit in mC9-MG drives increased vulnerability of mC9-MNs to excitotoxic stimulus. Pharmacological activation of autophagy ameliorated both cell-autonomous functional deficits in hiPSC-MG and MN death in MG-MN coculture. Together, these findings reveal an important role for C9ORF72 in regulating immune homeostasis and identify dysregulation in myeloid cells as a contributor to neurodegeneration in ALS/FTD.