Zhang, B.-Y. | Search bioRxiv

bioRxiv2023

Exploring the mechanisms and potential therapeutic targets of Ferroptosis Related Genes in ankylosing spondylitis

BackgroundFerroptosis is a novel type of regulated cell death, and there is growing evidence that it is directly associated with the disease. Therefore, this study aimed to investigate the relevance of iron Ferroptosis-related genes to ankylosing spondylitis (AS) to propose a novel targeted therapy for AS patients. MethodsAS samples were downloaded from the Gene Expression Omnibus (GEO) database (GSE41038). Ferroptosis-related genes were obtained from the FerrDb database, and differential expression analysis was performed using the GEO2R tool. Additionally, we constructed a protein-protein interaction (PPI) network and identified the central genes using Cytoscape. A neural network model was developed utilizing the data mining software Clementine. cMap technology was used to screen potential pharmacological compounds that target the central gene,and a predictive model was built by machine learning methods. ResultsWe discovered 786 differentially expressed genes in AS samples compared to normal tissue, including 359 up-regulated and 427 down-regulated genes. The intersection of ferroptosis-related genes and differential genes yielded 20 overlapping genes. We constructed a hub gene co-expression network with 20 nodes and 14 edges and obtained the ten most recommended drugs for AS. ConclusionBioinformatics analysis identified 20 potential genes associated with Ferroptosis in AS. Genes such as CAV1, NOX4, and NQO1 were revealed to influence the development of AS by regulating Ferroptosis. Our study provides new insights into the function of iron Ferroptosis-related genes in AS, suggesting that targeting Ferroptosis may be a potential therapeutic option for AS.

bioinformatics↗

bioRxiv2023

A cataract-causing Y204X mutation of CRYβB1 promotes C-terminal degradation and higher-order oligomerization

Crystallin (Cry) proteins are a class of main structural proteins of vertebrate eye lens, and their solubility and stability directly determine transparency and refractive power of the lens. Mutation in genes that encode for these Cry proteins is the common cause for congenital cataract. Despite extensive studies, the pathogenic and molecular mechanisms remain unclear. In this study, we identified a novel mutation in CRYBB1 from a congenital cataract family, and demonstrated that this mutation led to an earlier termination of protein translation, resulting in a 49-residue truncation at the CRY{beta}B1 C-terminus. This mutant is susceptible to proteolysis and allows us to determine a 1.2- [A] resolution crystal structure of CRY{beta}B1 without the entire C-terminal domain. In this crystal lattice, two N-terminal domain monomers form a dimer that structurally resembles a wild-type (WT) monomer, but with different surface characteristics. Biochemical analyses suggest that this mutant is significantly more liable to aggregate and degrade, when compared to WT CRY{beta}B1. All our results provide an insight into the mechanism regarding how a mutant Cry contributes to the development of congenital cataract possibly through alteration of inter-protein interactions that result in the opacity of eye lens.

biochemistry↗