E3 ubiquitin ligase Herc3 deficiency leads to accumulation of subretinal microglia and retinal neurodegeneration

Yeshumenesh Zegeye, Bogale Aredo, Seher Yuksel, Dogan Can Kirman, Ashwani Kumar, Bo Chen, Emily Turpin, Sangita Shresta, Yu Guang He, Laurent Gautron, Miao Tang, Xiaohong Li, Sophia M. DiCesare, John D Hulleman, Chao Xing, Sara Ludwig, Eva Marie Y. Moresco, Bruce A. Beutler, Rafael L. Ufret-Vincenty

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Activated microglia have been implicated in the pathogenesis of age-related macular degeneration (AMD), diabetic retinopathy, and other neurodegenerative and neuroinflammatory disorders, but our understanding of the mechanisms behind their activation is in infant stages. With the goal of identifying novel genes associated with microglial activation in the retina, we applied a semiquantitative fundus spot scoring scale to an unbiased, state-of-the-science mouse forward genetics pipeline. A mutation in the gene encoding the E3 ubiquitin ligase Herc3 led to prominent accumulation of fundus spots. CRISPR mutagenesis was used to generate Herc3-/- mice, which developed prominent accumulation of fundus spots and corresponding activated Iba1 + /CD16 + subretinal microglia, retinal thinning on OCT and histology, and functional deficits by Optomotory and electrophysiology. Bulk RNA sequencing identified activation of inflammatory pathways and differentially expressed genes involved in the modulation of microglial activation. Thus, despite the known expression of multiple E3 ubiquitin ligases in the retina, we identified a non-redundant role for Herc3 in retinal homeostasis. Our findings are significant given that a dysregulated ubiquitin–proteasome system (UPS) is important in prevalent retinal diseases, in which activated microglia appear to play a role. This association between Herc3 deficiency, retinal microglial activation and retinal degeneration merits further study.

Original languageEnglish (US)
JournalScientific reports
Volume14
Issue number1
DOIs
StatePublished - Dec 2024

Keywords

  • CRISPR
  • ENU-mutagenesis
  • Forward genetics
  • Fundus spots
  • Herc3
  • Microglia
  • Phenotype-genotype association
  • Retinal neurodegeneration
  • Screening

ASJC Scopus subject areas

  • General

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