Retinal transcriptome profiling identifies novel candidate genes associated with visual impairment in a mouse model of multiple sclerosis

by Selleckchem | Nov 24 2023

Visual impairment is occasionally observed in multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). Although uveitis and optic neuritis have been reported in MS and EAE, the precise mechanisms underlying the pathogenesis of these visual impairments remain poorly understood. This study aims to identify differentially expressed genes (DEGs) in the retinas of mice with EAE to identify genes that may be implicated in EAE-induced visual impairment. Fourteen adult mice were injected with myelin oligodendrocyte glycoprotein35-55 to induce the EAE model. Transcriptomes of retinas with EAE were analyzed by RNA-sequencing. Gene expression analysis revealed 347 DEGs in the retinas of mice with EAE: 345 were upregulated, and 2 were downregulated (adjusted p-value < 0.05 and absolute log2 fold change > 1). Gene ontology (GO) analysis showed that the upregulated genes in the retinas of mice with EAE were primarily related to immune responses, responses to external biotic stimuli, defense responses, and leukocyte-mediated immunity in the GO biological process. The expression of six upregulated hub genes (c1qb, ctss, itgam, itgb2, syk, and tyrobp) from the STRING analysis and the two significantly downregulated DEGs (hapln1 and ndst4) were validated by reverse transcription-quantitative polymerase chain reaction. In addition, gene set enrichment analysis showed that the negatively enriched gene sets in EAE-affected retinas were associated with the neuronal system and phototransduction cascade. This study provides novel molecular evidence for visual impairments in EAE and indicates directions for further research to elucidate the mechanisms of these visual impairments in MS.

Comments:

The study you described aimed to investigate the molecular mechanisms underlying visual impairments in experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis (MS). The researchers induced EAE in mice and analyzed the gene expression profiles in their retinas using RNA-sequencing. Here is a summary of the key findings and implications of the study:

### Key Findings:

1. **Differentially Expressed Genes (DEGs)**:
   - A total of 347 DEGs were identified in the retinas of mice with EAE. Among these, 345 genes were upregulated, and 2 genes were downregulated.

2. **Gene Ontology (GO) Analysis**:
   - Upregulated genes were primarily associated with immune responses, responses to external biotic stimuli, defense responses, and leukocyte-mediated immunity. These findings suggest a strong immune response component in the visual impairment observed in EAE.

3. **Hub Genes and Validation**:
   - Six upregulated hub genes (c1qb, ctss, itgam, itgb2, syk, and tyrobp) identified through protein-protein interaction analysis, along with two significantly downregulated genes (hapln1 and ndst4), were validated using reverse transcription-quantitative polymerase chain reaction (RT-qPCR).

4. **Gene Set Enrichment Analysis (GSEA)**:
- GSEA revealed that negatively enriched gene sets in EAE-affected retinas were associated with the neuronal system and phototransduction cascade. This implies that these pathways might be compromised in EAE-induced visual impairments.

### Implications and Future Directions:

1. **Immunological Basis of Visual Impairment**:
- The study strongly implicates immune-related pathways in EAE-induced visual impairments. Further research could focus on understanding how immune responses in the retina contribute to visual dysfunction in MS and EAE.

2. **Hub Genes as Potential Targets**:
- The validated hub genes, especially those related to immune responses, could be potential therapeutic targets for managing visual impairments in MS patients. Investigating these genes might reveal new avenues for treatment development.

3. **Neuronal and Phototransduction Pathways**:
- The compromised neuronal and phototransduction pathways suggest a potential link between neurological dysfunction and visual impairment in EAE. Studying these pathways in more detail could provide insights into the specific mechanisms leading to visual deficits.

4. **Translation to MS Research**:
- Since EAE is a model for MS, the findings of this study might have implications for understanding visual impairments in MS patients. Future research could explore whether similar molecular mechanisms are at play in human MS-related visual impairments.

In summary, this study sheds light on the molecular underpinnings of visual impairments in EAE, providing a foundation for further investigations into the mechanisms of visual dysfunction in both EAE and MS.