The Role of Autophagy–Lysosomal Pathways in Photoreceptor Death in the rd10 Mouse Model of Inherited Retinal Degeneration

TL;DR

This study explores how problems with cell waste disposal contribute to photoreceptor death in a mouse model of retinal degeneration, suggesting early treatment opportunities.

Contribution

The study identifies early autophagy–lysosomal changes in photoreceptor degeneration, highlighting a potential therapeutic window.

Findings

Autophagosome and autolysosome numbers increase in photoreceptor compartments before significant cell loss.

Early downregulation of mTOR and upregulation of autophagy-related genes suggest initial autophagy induction.

Progressive accumulation of unprocessed waste indicates overwhelmed cellular clearance capacity.

Abstract

Inherited retinal degenerations, such as retinitis pigmentosa, are a leading cause of irreversible vision loss, yet broadly effective treatments remain elusive. Impaired cellular waste clearance via autophagy–lysosomal pathways have been implicated in photoreceptor death, but the spatiotemporal dynamics of these processes during degeneration remain poorly understood. Using the rd10 mouse model of retinitis pigmentosa, we characterised autophagy–lysosomal dysfunction at key stages of photoreceptor degeneration (postnatal day P17, P22, P35) through super-resolution imaging of RFP-EGFP-LC3 reporter mice, Western blot, and bulk RNA sequencing. Autophagosome and autolysosome numbers were significantly elevated across all photoreceptor compartments (inner/outer segments, outer nuclear layer, outer plexiform layer) at P17, prior to significant photoreceptor nuclei loss. Autophagosome and autolysosome size progressively increased from P22 onwards, suggesting accumulation of unprocessed intracellular waste. Molecular analyses revealed downregulation of mTOR protein, upregulation of autophagy-related genes, and increased lysosomal processes from P17. These histological and molecular findings are consistent with early autophagy induction followed by overwhelmed degradative capacity. Our findings identify autophagy–lysosomal change as an early event in photoreceptor loss in the rd10 model, revealing a critical therapeutic window for mutation-independent interventions targeting cellular clearance pathways in inherited retinal degenerations.

Figures