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

TitleLoss of APOBEC1 RNA-editing function in microglia exacerbates age-related CNS pathophysiology.
Publication TypeJournal Article
Year of Publication2017
AuthorsCole DC, Chung Y, Gagnidze K, Hajdarovic KH, Rayon-Estrada V, Harjanto D, Bigio B, Gal-Toth J, Milner TA, McEwen BS, F Papavasiliou N, Bulloch K
JournalProc Natl Acad Sci U S A
Volume114
Issue50
Pagination13272-13277
Date Published2017 Dec 12
ISSN1091-6490
Abstract

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.

DOI10.1073/pnas.1710493114
Alternate JournalProc. Natl. Acad. Sci. U.S.A.
PubMed ID29167375
PubMed Central IDPMC5740644
Grant ListP01 HL096571 / HL / NHLBI NIH HHS / United States
R01 CA098495 / CA / NCI NIH HHS / United States
R01 DA008259 / DA / NIDA NIH HHS / United States