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E3 ubiquitin ligase Herc3 deficiency leads to accumulation of subretinal microglia and retinal neurodegeneration.
Zegeye, Yeshumenesh; Aredo, Bogale; Yuksel, Seher; Kirman, Dogan Can; Kumar, Ashwani; Chen, Bo; Turpin, Emily; Shresta, Sangita; He, Yu-Guang; Gautron, Laurent; Tang, Miao; Li, Xiaohong; DiCesare, Sophia M; Hulleman, John D; Xing, Chao; Ludwig, Sara; Moresco, Eva Marie Y; Beutler, Bruce A; Ufret-Vincenty, Rafael L.
Afiliación
  • Zegeye Y; Department of Ophthalmology, UT Southwestern Medical Center, Dallas, TX, USA.
  • Aredo B; Department of Ophthalmology, UT Southwestern Medical Center, Dallas, TX, USA.
  • Yuksel S; Department of Ophthalmology, UT Southwestern Medical Center, Dallas, TX, USA.
  • Kirman DC; Department of Ophthalmology, UT Southwestern Medical Center, Dallas, TX, USA.
  • Kumar A; McDermott Center for Human Growth and Development, UT Southwestern Medical Center, Dallas, TX, USA.
  • Chen B; Department of Ophthalmology, UT Southwestern Medical Center, Dallas, TX, USA.
  • Turpin E; Department of Ophthalmology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
  • Shresta S; Department of Ophthalmology, UT Southwestern Medical Center, Dallas, TX, USA.
  • He YG; Department of Ophthalmology, UT Southwestern Medical Center, Dallas, TX, USA.
  • Gautron L; Department of Ophthalmology, UT Southwestern Medical Center, Dallas, TX, USA.
  • Tang M; Center for Hypothalamic Research and Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA.
  • Li X; Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • DiCesare SM; Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • Hulleman JD; Department of Ophthalmology, UT Southwestern Medical Center, Dallas, TX, USA.
  • Xing C; Department of Ophthalmology, UT Southwestern Medical Center, Dallas, TX, USA.
  • Ludwig S; McDermott Center for Human Growth and Development, UT Southwestern Medical Center, Dallas, TX, USA.
  • Moresco EMY; Department of Bioinformatics, UT Southwestern Medical Center, Dallas, TX, USA.
  • Beutler BA; Center for Hypothalamic Research and Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA.
  • Ufret-Vincenty RL; Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Sci Rep ; 14(1): 3010, 2024 02 06.
Article en En | MEDLINE | ID: mdl-38321224
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Degeneración Retiniana / Microglía Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Revista: Sci Rep Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Degeneración Retiniana / Microglía Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Revista: Sci Rep Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido