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

Abstract

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.

Suppressor of Cytokine Signaling 3 Derived Peptide as a Therapeutic for Inflammatory, and Oxidative Stress Induced Damage to the Retina

“…Increased levels of TNFα have been reported to contribute to choroidal neovascularization and to stimulate epithelial to mesenchymal transition in the RPE (35, 36). We therefore tested the effect of TNFα on RPE cells.…”

Pathological features and molecular signatures of early olfactory dysfunction in 3xTg‐AD model mice

“…Nr4a2 reduction has also been implicated in depression, where it mediates the decrease in neuronal activity induced by lipopolysaccharide (LPS), leading to the development of depressive symptoms 17 . Furthermore, Nr4a2 is associated with age‐related macular degeneration, 31 attention deficit hyperactivity disorder, 32 cardiovascular abnormalities, 33 and neuroinflammation in the brains of patients with Parkinson's disease (PD) 34 . FosB is indeed a member of the Fos family of transcription factors, 35 which is part of the AP‐1 transcription factor complex and are involved in regulating gene expression 36 .…”

Impaired ATF3 signaling involves SNAP25 in SOD1 mutant ALS patients

“…Nuclear receptor subfamily 4 group A, or simply NR4A, proteins for instance are nuclear receptor (NR) transcription factors that play a regulatory role in neuronal development, inflammation, and memory formation 29 . The associated disorders are related to dopaminergic dysfunction, including PD, schizophrenia, and manic depression 30 , 31 . GADD45B, on the other hand, is a neuronal activity sensor induced by neuronal stress and essential for adult neurogenesis 32 .…”