Fat mass and obesity-associated protein alleviates Aβ1-40 induced retinal pigment epithelial cells degeneration via PKA/CREB signaling pathway.

Abstract

Amyloid-β (Aβ) is thought to be a critical pathologic factor of retinal pigment epithelium (RPE) degeneration in age-related macular degeneration (AMD). Aβ induces inflammatory responses in RPE cells and recent studies demonstrate the N6-methyladenosine (m6A) regulatory role in RPE cell inflammation. m6A is a reversible epigenetic posttranslational modification, but its relationship with Aβ-induced RPE degeneration is yet to be thoroughly investigated. The present study explored the role and mechanism of m6A in Aβ-induced RPE degeneration model. This model was induced via intravitreally injecting oligomeric Aβ and the morphology of its retina was analyzed. One of m6A demethylases, the fat mass and obesity-associated (FTO) gene expression, was assessed. An m6A-messenger RNA (mRNA) epitranscriptomic microarray was employed for further bioinformatic analyses. It was confirmed that Aβ induced FTO upregulation within the RPE. Hypopigmentation alterations and structural disorganization were observed in Aβ-treated eyes, and inhibition of FTO exacerbated retinal degeneration and RPE impairment. Moreover, the m6A-mRNA epitranscriptomic microarray suggested that protein kinase A (PKA) was a target of FTO, and the PKA/cyclic AMP-responsive element binding (CREB) signaling pathway was involved in Aβ-induced RPE degeneration. m6A-RNA binding protein immunoprecipitation confirmed that FTO demethylated PKA within the RPE cells of Aβ-treated eyes. Altered expression of PKA and its downstream targets (CREB and brain-derived neurotrophic factor) was confirmed by quantitative reverse-transcription polymerase chain reaction and Western blot analyses. Hence, this study's findings shed light on FTO-mediated m6A modification in Aβ-induced RPE degeneration and indicate potential therapeutic targets for AMD.

• Authors: Yifan Hu, Jieqiong Chen, Yuwei Wang, Junran Sun, Peirong Huang, Jingyang Feng, Te Liu, Xiaodong Sun
• Journal: Cell biology international (Cell Biol Int) Vol. 47 Issue 3 Pg. 584-597 (Mar 2023) ISSN: 1095-8355 [Electronic] England
• PMID: 36378581 (Publication Type: Journal Article)
• Copyright: © 2022 International Federation for Cell Biology.

Chemical References

• Amyloid beta-Peptides
• RNA, Messenger
• Retinal Pigments
• FTO protein, human
• Alpha-Ketoglutarate-Dependent Dioxygenase FTO

Topics

• Humans
• Retina (metabolism)
• Macular Degeneration (metabolism)
• Amyloid beta-Peptides (metabolism)
• Signal Transduction
• RNA, Messenger (metabolism)
• Obesity (metabolism)
• Epithelial Cells (metabolism)
• Retinal Pigments (metabolism)
• Alpha-Ketoglutarate-Dependent Dioxygenase FTO