Autophagy disruption and mitochondrial stress precede photoreceptor necroptosis in multiple mouse models of inherited retinal disorders

Pleased to share our latest pre-print work led by Fay Newton on using scRNASeq to identify common cellular mechanisms by which photoreceptors die in multiple mouse models of IRD.

https://www.biorxiv.org/content/10.1101/2024.08.02.606303v1

Inherited retinal disorders (IRDs) are the leading cause of sight loss in children and working adults. Mutations in one of over 280 genes lead to death of the light sensing photoreceptors in the eye. IRDs remain largely untreatable and so a better understanding of disease mechanism is therefore required.

In our study, we used single cell RNA sequencing, advanced imaging and humanised mouse models to show how IRD photoreceptors require increase rates of autophagy as they become stressed, in order to clear damaged proteins or organelles.

Later, the photoreceptors develop increasingly dysfunctional mitochondria, the energy generators within the cell. As a result, the energy production of these mitochondria are compromised.

Finally, we have determined that necroptosis is the main cell death pathway that leads to photoreceptor degeneration.

Crucially, we show that these defects occur in several IRD models, each carrying mutations in genes involved in different cell pathways. This indicates that common pathways could be targetable to halt photoreceptor degeneration in IRDs in a gene-agnostic fashion.

This study, funded by Fight For Sight UK and Wellcome sheds real light on the pathogenesis of an untreatable disease. Further work will determine if this could be developed into a realistic therapeutic strategy.