Skip to main content
Journal cover image

NURR1 expression regulates retinal pigment epithelial-mesenchymal transition and age-related macular degeneration phenotypes.

Publication ,  Journal Article
Yao, P-L; Parmar, VM; Choudhary, M; Malek, G
Published in: Proc Natl Acad Sci U S A
July 12, 2022

Phenotypic variations in the retinal pigment epithelial (RPE) layer are often a predecessor and driver of ocular degenerative diseases, such as age-related macular degeneration (AMD), the leading cause of vision loss in the elderly. We previously identified the orphan nuclear receptor-related 1 (NURR1), from a nuclear receptor atlas of human RPE cells, as a candidate transcription factor potentially involved in AMD development and progression. In the present study we characterized the expression of NURR1 as a function of age in RPE cells harvested from human donor eyes and in donor tissue from AMD patients. Mechanistically, we found an age-dependent shift in NURR1 dimerization from NURR1-RXRα heterodimers toward NURR1-NURR1 homodimers in primary human RPE cells. Additionally, overexpression and activation of NURR1 attenuated TNF-α-induced epithelial-to-mesenchymal transition (EMT) and migration, and modulated EMT-associated gene and protein expression in human RPE cells independent of age. In vivo, oral administration of IP7e, a potent NURR1 activator, ameliorated EMT in an experimental model of wet AMD and improved retinal function in a mouse model that presents with dry AMD features, impacting AMD phenotype, structure, and function of RPE cells, inhibiting accumulation of immune cells, and diminishing lipid accumulation. These results provide insight into the mechanisms of action of NURR1 in the aging eye, and demonstrate that the relative expression levels and activity of NURR1 is critical for both physiological and pathological functions of human RPE cells through RXRα-dependent regulation, and that targeting NURR1 may have therapeutic potential for AMD by modulating EMT, inflammation, and lipid homeostasis.

Duke Scholars

Altmetric Attention Stats
Dimensions Citation Stats

Published In

Proc Natl Acad Sci U S A

DOI

EISSN

1091-6490

Publication Date

July 12, 2022

Volume

119

Issue

28

Start / End Page

e2202256119

Location

United States

Related Subject Headings

  • Retinal Pigment Epithelium
  • Protein Multimerization
  • Phenotype
  • Nuclear Receptor Subfamily 4, Group A, Member 2
  • Mice
  • Macular Degeneration
  • Lipids
  • Humans
  • Epithelial-Mesenchymal Transition
  • Animals
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Yao, P.-L., Parmar, V. M., Choudhary, M., & Malek, G. (2022). NURR1 expression regulates retinal pigment epithelial-mesenchymal transition and age-related macular degeneration phenotypes. Proc Natl Acad Sci U S A, 119(28), e2202256119. https://doi.org/10.1073/pnas.2202256119
Yao, Pei-Li, Vipul M. Parmar, Mayur Choudhary, and Goldis Malek. “NURR1 expression regulates retinal pigment epithelial-mesenchymal transition and age-related macular degeneration phenotypes.Proc Natl Acad Sci U S A 119, no. 28 (July 12, 2022): e2202256119. https://doi.org/10.1073/pnas.2202256119.
Yao P-L, Parmar VM, Choudhary M, Malek G. NURR1 expression regulates retinal pigment epithelial-mesenchymal transition and age-related macular degeneration phenotypes. Proc Natl Acad Sci U S A. 2022 Jul 12;119(28):e2202256119.
Yao, Pei-Li, et al. “NURR1 expression regulates retinal pigment epithelial-mesenchymal transition and age-related macular degeneration phenotypes.Proc Natl Acad Sci U S A, vol. 119, no. 28, July 2022, p. e2202256119. Pubmed, doi:10.1073/pnas.2202256119.
Yao P-L, Parmar VM, Choudhary M, Malek G. NURR1 expression regulates retinal pigment epithelial-mesenchymal transition and age-related macular degeneration phenotypes. Proc Natl Acad Sci U S A. 2022 Jul 12;119(28):e2202256119.
Journal cover image

Published In

Proc Natl Acad Sci U S A

DOI

EISSN

1091-6490

Publication Date

July 12, 2022

Volume

119

Issue

28

Start / End Page

e2202256119

Location

United States

Related Subject Headings

  • Retinal Pigment Epithelium
  • Protein Multimerization
  • Phenotype
  • Nuclear Receptor Subfamily 4, Group A, Member 2
  • Mice
  • Macular Degeneration
  • Lipids
  • Humans
  • Epithelial-Mesenchymal Transition
  • Animals