bims-mideyd 2024-05-19 papers

Issue of 2024‒05‒19
four papers selected by
Rajalekshmy “Raji” Shyam, Indiana University Bloomington

Hum Cell. 2024 May 14.

CYTOR-NFAT1 feedback loop regulates epithelial-mesenchymal transition of retinal pigment epithelial cells.

Rong Zhang, Lin Wang, Yang Li, Yan Liu, Kui Dong, Yajing Pei, Junmei Zhao, Gang Liu, Jing Li, Xiaodan Zhang, Tong Cui, Yan Gao, Wenjuan Wang, Yongrui Wang, Chenwei Gui, Guohong Zhou.

Epithelial mesenchymal transition (EMT) occurring in retinal pigment epithelial cells (RPE) is a crucial mechanism that contributes to the development of age-related macular degeneration (AMD), a pivotal factor leading to permanent vision impairment. Long non-coding RNAs (lncRNAs) have emerged as critical regulators orchestrating EMT in RPE cells. In this study, we explored the function of the lncRNA CYTOR (cytoskeleton regulator RNA) in EMT of RPE cells and its underlying mechanisms. Through weighted correlation network analysis, we identified CYTOR as an EMT-related lncRNA associated with AMD. Experimental validation revealed that CYTOR orchestrates TGF-β1-induced EMT, as well as proliferation and migration of ARPE-19 cells. Further investigation demonstrated the involvement of CYTOR in regulating the WNT5A/NFAT1 pathway and NFAT1 intranuclear translocation in the ARPE-19 cell EMT model. Mechanistically, CHIP, EMSA and dual luciferase reporter assays confirmed NFAT1's direct binding to CYTOR's promoter, promoting transcription. Reciprocally, CYTOR overexpression promoted NFAT1 expression, while NFAT1 overexpression increased CYTOR transcription. These findings highlight a mutual promotion between CYTOR and NFAT1, forming a positive feedback loop that triggers the EMT phenotype in ARPE-19 cells. These discoveries provide valuable insights into the molecular mechanisms of EMT and its association with AMD, offering potential avenues for targeted therapies in EMT-related conditions, including AMD.

Keywords: Age-related macular degeneration; Biomarker; Epithelial mesenchymal transition; Long non-coding RNA; Positive feedback loop

DOI: https://doi.org/10.1007/s13577-024-01075-w

Aging Dis. 2024 Apr 22.

Ammaji Rajala, Raju V S Rajala.

Prior studies have emphasized a bioenergetic crisis in the retinal pigment epithelium (RPE) as a critical factor in the development of age-related macular degeneration (AMD). The isoforms Fructose-1,6-bisphosphate aldolase C (ALDOC) and pyruvate kinase M2 (PKM2) have been proposed to play a role in AMD pathogenesis. While PKM2 and ALDOC are crucial for aerobic glycolysis in the neural retina, they are not as essential for the RPE. In this study, we examined the expression and activity of PKM2 and ALDOC in both young and aged RPE cells, as well as in the retina and RPE tissue of mice, including an experimentally induced AMD mouse model. Our findings reveal an upregulation in PKM2 and ALDOC expression, accompanied by increased pyruvate kinase activity, in the aged and AMD mouse RPE. Conversely, there is a decrease in ALDOC expression but an increase in PKM2 expression and pyruvate kinase activity in the aged and AMD retina. Overall, our study indicates that aged and AMD RPE cells tend to favor aerobic glycolysis, while this tendency is diminished in the aged and AMD retina. These results underscore the significance of targeting PKM2 and ALDOC in the RPE as a promising therapeutic approach to address the bioenergetic crisis and prevent vision loss in AMD.

DOI: https://doi.org/10.14336/AD.2024.0077

Gene Ther. 2024 May 16.

Retinoic acid related orphan receptor α is a genetic modifier that rescues retinal degeneration in a mouse model of Stargardt disease and Dry AMD.

M Akula, S M McNamee, Z Love, N Nasraty, N P M Chan, M Whalen, M O Avola, A M Olivares, B D Leehy, A S Jelcick, P Singh, A K Upadhyay, D F Chen, N B Haider.

Degeneration of the macula is associated with several overlapping diseases including age-related macular degeneration (AMD) and Stargardt Disease (STGD). Mutations in ATP Binding Cassette Subfamily A Member 4 (ABCA4) are associated with late-onset dry AMD and early-onset STGD. Additionally, both forms of macular degeneration exhibit deposition of subretinal material and photoreceptor degeneration. Retinoic acid related orphan receptor α (RORA) regulates the AMD inflammation pathway that includes ABCA4, CD59, C3 and C5. In this translational study, we examined the efficacy of RORA at attenuating retinal degeneration and improving the inflammatory response in Abca4 knockout (Abca4-/-) mice. AAV5-hRORA-treated mice showed reduced deposits, restored CD59 expression and attenuated amyloid precursor protein (APP) expression compared with untreated eyes. This molecular rescue correlated with statistically significant improvement in photoreceptor function. This is the first study evaluating the impact of RORA modifier gene therapy on rescuing retinal degeneration. Our studies demonstrate efficacy of RORA in improving STGD and dry AMD-like disease.

DOI: https://doi.org/10.1038/s41434-024-00455-z

Aging (Albany NY). 2024 May 10. 16

Bioinformatics analysis for constructing a cellular senescence-related age-related macular degeneration diagnostic model and identifying relevant disease subtypes to guide treatment.

Shan Luo, Qiang Hu, Bo Jiang, Zhongyu Zhang, Dawei Sun.

Age-related macular degeneration (AMD) is a condition causing progressive central vision loss. Growing evidence suggests a link between cellular senescence and AMD. However, the exact mechanism by which cellular senescence leads to AMD remains unclear. Employing machine learning, we established an AMD diagnostic model. Through unsupervised clustering, two distinct AMD subtypes were identified. GO, KEGG, and GSVA analyses explored the diverse biological functions associated with the two subtypes. By WGCNA, we constructed a coexpression network of differential genes between the subtypes, revealing the regulatory role of hub genes at the level of transcription factors and miRNAs. We identified 5 genes associated with inflammation for the construction of the AMD diagnostic model. Additionally, we observed that the level of cellular senescence and pathways related to programmed cell death (PCD), such as ferroptosis, necroptosis, and pyroptosis, exhibited higher expression levels in subtype B than A. Immune microenvironments also differed between the subtypes, indicating potentially distinct pathogenic mechanisms and therapeutic targets. In summary, by leveraging cellular senescence-associated gene expression, we developed an AMD diagnostic model. Furthermore, we identified two subtypes with varying expression patterns of senescence genes, revealing their differential roles in programmed cell death, disease progression, and immune microenvironments within AMD.

Keywords: age-related macular degeneration; cellular senescence; inflammatory response; molecular subtypes; programmed cell death

DOI: https://doi.org/10.18632/aging.205804