Single-Cell Transcriptomics on PRPF31-Mutated Retinal Organoids Reveal Early Müller Glial Activation and Progressive...

Area of Science:

• Genetics and Molecular Biology
• Ophthalmology
• Cell Biology

Background:

• Retinitis pigmentosa (RP) comprises inherited retinal disorders causing photoreceptor degeneration and vision loss.
• RP11 subtype is linked to mutations in the spliceosome gene PRPF31, primarily affecting retinal cells.
• Limited understanding exists regarding early molecular events and non-photoreceptor cell involvement in RP11 pathogenesis.

Purpose of the Study:

• To investigate the impact of PRPF31 mutations in RP11 using patient-derived retinal organoids (ROs).
• To elucidate early molecular events and cellular responses across all retinal cell types in RP11.
• To establish a comprehensive single-cell transcriptomic profile of RP11.

Main Methods:

• Generation and analysis of patient-derived retinal organoids (ROs).
• Morphological, functional, molecular, and transcriptomic analyses were performed.
• Single-cell RNA sequencing (scRNA-seq) was employed to capture dynamic transcriptional changes.

Main Results:

• scRNA-seq identified early Müller glia activation, retinal ganglion cell distress, and progressive photoreceptor degeneration.
• Dysregulated pathways in phototransduction, oxidative stress, and inflammation were discovered.
• PRPF31 mutations were shown to recapitulate key RP features in vitro.

Conclusions:

• The study establishes a relevant RO model for RP11.
• PRPF31 mutations trigger compensatory and modulatory responses in other retinal cell types.
• Findings provide insights into the complex cellular dynamics of inherited retinal degeneration.