Hsp90-associated DNA replication checkpoint protein and proteasome-subunit components are involved in the age-related macular degeneration
Age-related macular degeneration (AMD) is a leading cause of vision loss globally, particularly affecting the elderly population. Despite its significant impact on public health, the molecular mechanisms underlying AMD development and progression remain poorly understood. This study aims to explore the critical genes involved in AMD progression, focusing on the retinal pigment epithelium (RPE) and its role in the disease.
AMD is clinically classified into early-stage and late-stage forms. Early-stage AMD is characterized by the accumulation of drusen and abnormalities in the RPE, while late-stage AMD involves choroidal neovascularization (CNV) or geographic atrophy (GA). The global prevalence of AMD is increasing, with an estimated 288 million cases expected by 2040. Current treatments, such as anti-VEGF therapies, have reduced the incidence of vision impairment, but there are no effective therapies for atrophic AMD. Therefore, understanding the molecular mechanisms of AMD is crucial for developing new therapeutic strategies.
The RPE plays a vital role in maintaining retinal health by protecting the retina from systemic insults and facilitating the transport of nutrients and waste products. Damage to the RPE is a hallmark of AMD, leading to the loss of photoreceptor cells over time. Senescence of the RPE, induced by the depletion of nicotinamide adenine dinucleotide (NAD+), has been found to play a critical role in AMD progression. Impaired autophagy in RPE cells has also been linked to AMD development. Gene mutations or expression alterations in the RPE contribute to the pathogenesis of AMD, highlighting the importance of studying RPE gene expression profiles.
In this study, we analyzed differentially expressed genes (DEGs) in AMD RPE/choroid tissues using microarray datasets GSE99248 and GSE125564 from the Gene Expression Omnibus (GEO) database. We identified 174 DEGs in AMD RPE compared to healthy controls. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses revealed that these DEGs are primarily involved in the regulation of DNA replication, cell cycle, and proteasome-mediated protein polyubiquitination. Protein-protein interaction (PPI) network analysis identified the top ten hub genes, including HSP90AA1, CHEK1, PSMA4, PSMD4, and PSMD8, which were upregulated in senescent ARPE-19 cells.
HSP90AA1 encodes Hsp90, a chaperone protein essential for the correct folding and stabilization of various cellular proteins. Hsp90 has been implicated in AMD, and Hsp90 inhibitors have been used in clinical trials for AMD treatment. CHEK1 encodes the cell cycle checkpoint kinase Chk1, which regulates DNA replication and aging. Chk1 is an Hsp90 client, requiring Hsp90 for its kinase activity. PSMA4, PSMD4, and PSMD8 are proteasomal subunit components involved in protein degradation. The upregulation of these genes in senescent RPE cells suggests their involvement in AMD progression.
To further investigate the role of these hub genes in AMD, we induced senescence in ARPE-19 cells using FK866, a selective inhibitor of nicotinamide phosphoribosyltransferase (NAMPT), which reduces NAD+ levels. We found that HSP90AA1, CHEK1, PSMA4, PSMD4, and PSMD8 were upregulated in FK866-treated ARPE-19 cells, confirming their role in RPE senescence and AMD progression. HSP90AA1 was particularly sensitive to low doses of FK866, indicating its central role in RPE senescence.
We also explored potential therapeutic strategies by predicting small molecule drugs targeting the AMD-related key genes. Hsp90 inhibitors such as geldanamycin and its derivatives have shown promise in AMD treatment. BX795, a Chk1 inhibitor, has been shown to suppress inflammation and is safe for eye treatment. Bortezomib, a proteasome inhibitor, has potential anti-tumor activities and may also be effective in AMD treatment.
In addition to small molecule drugs, we investigated the role of microRNAs (miRNAs) in regulating the expression of AMD-related genes. miRNAs are small non-coding RNAs that regulate gene expression post-transcriptionally. We identified hsa-miR-16-5p as a potential regulator of HSP90AA1, CHEK1, PSMD4, and PSMD8. Hsa-miR-16-5p has been implicated in the regulation of inflammation and may play a role in AMD progression by targeting these key genes.
In conclusion, this study highlights the critical role of HSP90AA1, CHEK1, PSMA4, PSMD4, and PSMD8 in AMD progression through their involvement in RPE senescence. Targeting these genes with specific miRNAs or small molecules may provide new therapeutic strategies for AMD. Further research is needed to validate these findings and explore the potential of these therapeutic targets in clinical settings.
doi.org/10.1097/CM9.0000000000001773
Was this helpful?
0 / 0