Loss of APOBEC1 RNA-editing function in microglia exacerbates age-related CNS pathophysiology

被引:35
作者
Cole, Daniel C. [1 ,2 ]
Chung, Youngcheul [1 ,2 ]
Gagnidze, Khatuna [1 ,2 ]
Hajdarovic, Kaitlyn H. [1 ,2 ]
Rayon-Estrada, Violeta [3 ,4 ]
Harjanto, Dewi [3 ]
Bigio, Benedetta [2 ]
Gal-Toth, Judit [1 ,2 ]
Milner, Teresa A. [2 ,5 ]
McEwen, Bruce S. [2 ]
Papavasiliou, F. Nina [3 ,6 ]
Bulloch, Karen [1 ]
机构
[1] Rockefeller Univ, Neuroimmunol & Inflammat Program, New York, NY 10065 USA
[2] Rockefeller Univ, Lab Neuroendocrinol, New York, NY 10065 USA
[3] Rockefeller Univ, Lab Lymphocyte Biol, New York, NY 10065 USA
[4] Rockefeller Univ, Rockefeller Grad Program, New York, NY 10065 USA
[5] Weill Cornell Med, Feil Family Brain & Mind Res Inst, New York, NY 10065 USA
[6] German Canc Res Ctr, Div Immune Divers, D-69120 Heidelberg, Germany
基金
欧洲研究理事会;
关键词
microglia; RNA editing; lysosome; aging; neuroinflammation; CENTRAL-NERVOUS-SYSTEM; CHAPERONE-MEDIATED AUTOPHAGY; LAMP-2; DEFICIENCY; DANON-DISEASE; MOUSE MODEL; LYSOSOMAL DYSFUNCTION; INDUCED ENCEPHALITIS; DENDRITIC CELLS; INNATE IMMUNITY; CLEARANCE;
D O I
10.1073/pnas.1710493114
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Microglia (MG), a heterogeneous population of phagocytic cells, play important roles in central nervous system (CNS) homeostasis and neural plasticity. Under steady-state conditions, MG maintain homeostasis by producing antiinflammatory cytokines and neurotrophic factors, support myelin production, and remove synapses and cellular debris, as well as participating in "cross-correction," a process that supplies neurons with key factors for executing autophagy-lysosomal function. As sentinels for the immune system, MG also detect "danger" signals (pathogenic or traumatic insult), become activated, produce proinflammatory cytokines, and recruit monocytes and dendritic cells to the site of damage through a breached blood-brain barrier or via brain lymphatics. Failure to effectively resolve MG activation can be problematic and can lead to chronic inflammation, a condition proposed to underlie CNS pathophysiology in heritable brain disorders and age-related neurodegenerative and cognitive decline. Here, we show that APOBEC1-mediated RNA editing occurs within MG and is key to maintaining their resting status. Like bone marrow-derived macrophages, RNA editing in MG leads to overall changes in the abundance of edited proteins that coordinate the function of multiple cellular pathways. Conversely, mice lacking the APOBEC1 editing function in MG display evidence of dysregulation, with progressive age-related signs of neurodegeneration, characterized by clustering of activated MG, aberrant myelination, increased inflammation, and lysosomal anomalies that culminate in behavioral and motor deficiencies. Collectively, our study identifies posttranscriptional modification by RNA editing as a critical regulatory mechanism of vital cellular functions that maintain overall brain health.
引用
收藏
页码:13272 / 13277
页数:6
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