Intrinsic DNA damage repair deficiency results in progressive microglia loss and replacement

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Abstract

The DNA excision repair protein Ercc1 is important for nucleotide excision, double strand DNA break, and interstrand DNA crosslink repair. In constitutiveErcc1-knockout mice, microglia display increased phagocytosis, proliferation and an enhanced responsiveness to lipopolysaccharide (LPS)-induced peripheral inflammation. However, the intrinsic effects ofErcc1-deficiency on microglia are unclear. In this study,Ercc1was specifically deleted from Cx3cr1-expressing cells and changes in microglia morphology and immune responses at different times after deletion were determined. Microglia numbers were reduced with approximately 50% at 2-12 months afterErcc1deletion. Larger and more ramified microglia were observed followingErcc1deletion both in vivo and in organotypic hippocampal slice cultures.Ercc1-deficient microglia were progressively lost, and during this period, microglia proliferation was transiently increased.Ercc1-deficient microglia were gradually replaced by nondeficient microglia carrying a functionalErcc1allele. In contrast to constitutiveErcc1-deficient mice, microglia-specific deletion ofErcc1did not induce microglia activation or increase their responsiveness to a systemic LPS challenge. Gene expression analysis suggested thatErcc1deletion in microglia induced a transient aging signature, which was different from a priming or disease-associated microglia gene expression profile.

Original languageEnglish
Article number23925
Pages (from-to)1-17
Number of pages17
JournalGlia
Issue number3
DOIs
Publication statusPublished - 17-Oct-2020

Keywords

  • aging
  • DNA damage repair
  • Ercc1
  • microglia
  • morphometrics
  • DNA-DAMAGE
  • MOUSE MODEL
  • CELL
  • NEURODEGENERATION
  • REVEALS
  • REPOPULATION
  • ABLATION
  • AGE
  • TURNOVER

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