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.
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DOI：
10.1126/sciadv.abq0651
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发表时间：
2023-04-21
期刊：
影响因子：
13.6
通讯作者：
中科院分区：
文献类型：
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作者：
尽管小胶质细胞激活在肌萎缩侧索硬化症（ALS）和额颞叶痴呆（FTD）中广泛发现，但其潜在机制尚不清楚。在这里，我们使用人类诱导的多能干细胞衍生的小胶质样细胞（hiPSC-MG），其中包含最常见的ALS/FTD突变（C9orf72, mC9-MG），基因校正的等基因对照（iso9 - mg）和C9orf72敲除的hiPSC-MG (C9KO-MG)，我们发现C9orf72蛋白的减少与脂多糖刺激下的吞噬功能受损和夸大的免疫反应有关。对C9ORF72相互作用组的分析显示，C9ORF72与自噬调节因子相互作用，功能研究显示mC9-MG和C9KO-MG的自噬起始受损。与运动神经元（MNs）共培养的研究表明，mC9-MG的自噬缺陷导致mC9-MNs对兴奋毒性刺激的易感性增加。自噬的药理激活改善了hiPSC-MG的细胞自主功能缺陷和MG-MN共培养的MN死亡。总之，这些发现揭示了C9ORF72在调节免疫稳态中的重要作用，并确定髓细胞失调是ALS/FTD神经退行性变的一个因素。在C9orf72-ALS中，自噬中断导致的小胶质细胞免疫激活有助于增强运动神经元的死亡。
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), and C9orf72 knockout 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. Disrupted autophagy led immune activation in microglia contributes to enhanced motor neuronal death in C9orf72-ALS.
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DOI：
10.1126/science.aaa3650
发表时间：
2015-03-27
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Cirulli ET;Lasseigne BN;Petrovski S;Sapp PC;Dion PA;Leblond CS;Couthouis J;Lu YF;Wang Q;Krueger BJ;Ren Z;Keebler J;Han Y;Levy SE;Boone BE;Wimbish JR;Waite LL;Jones AL;Carulli JP;Day-Williams AG;Staropoli JF;Xin WW;Chesi A;Raphael AR;McKenna-Yasek D;Cady J;Vianney de Jong JM;Kenna KP;Smith BN;Topp S;Miller J;Gkazi A;FALS Sequencing Consortium;Al-Chalabi A;van den Berg LH;Veldink J;Silani V;Ticozzi N;Shaw CE;Baloh RH;Appel S;Simpson E;Lagier-Tourenne C;Pulst SM;Gibson S;Trojanowski JQ;Elman L;McCluskey L;Grossman M;Shneider NA;Chung WK;Ravits JM;Glass JD;Sims KB;Van Deerlin VM;Maniatis T;Hayes SD;Ordureau A;Swarup S;Landers J;Baas F;Allen AS;Bedlack RS;Harper JW;Gitler AD;Rouleau GA;Brown R;Harms MB;Cooper GM;Harris T;Myers RM;Goldstein DB
通讯作者：
Goldstein DB
影响因子：
14.8
作者：
Barmada, Sami J.;Serio, Andrea;Arjun, Arpana;Bilican, Bilada;Daub, Aaron;Ando, D. Michael;Tsvetkov, Andrey;Pleiss, Michael;Li, Xingli;Peisach, Daniel;Shaw, Christopher;Chandran, Siddharthan;Finkbeiner, Steven
通讯作者：
Finkbeiner, Steven
影响因子：
16.6
作者：
Choi, Insup;Zhang, Yuanxi;Yue, Zhenyu
通讯作者：
Yue, Zhenyu
影响因子：
48
作者：
Gibson, Daniel G.;Young, Lei;Smith, Hamilton O.
通讯作者：
Smith, Hamilton O.
影响因子：
6.2
作者：
Deora, Vandana;Lee, John D.;Woodruff, Trent M.
通讯作者：
Woodruff, Trent M.