Eye colour genes important for a healthy retina

Many human diseases, including retinal and other neurodegenerative diseases, are associated with disturbances in metabolic pathways. Elisabeth Knust and her team at the Max Planck Institute of Molecular Cell Biology and Genetics in Dresden have investigated the role of such a metabolic pathway in maintaining retinal health under stress conditions. They focused on the classical genes cinnabar, cardinal, white and scarlet of the fruit fly Drosophila, which were characterised decades ago for their role in the formation of eye colour, in particular the brown pigment. These genes encode components of the kynurenine metabolic pathway. In a recent study, the authors have discovered a new function of this pathway in retinal health that is independent of its role in pigment formation.

The evolutionarily conserved kynurenine metabolic pathway regulates a variety of biological processes. Disruption or defective activity can lead to the formation of toxic or damaging biomolecules or metabolites that can worsen or improve brain health, including retinal health. The research team, led by Elisabeth Knust, an emeritus director of the Max Planck Institute of Molecular Cell Biology and Genetics, has recently expanded our knowledge of this important metabolic pathway through a publication.

Knowing the remarkable conservation of this pathway and the genes that regulate it, the team worked with flies as a model organism to explore the role of individual metabolites in retinal health. The researchers studied four fly genes - cinnabar, cardinal, white and scarlet - named after a change in eye colour after loss. „Since the kynurenine metabolic pathway is conserved from flies to humans, we wondered whether these genes regulate retinal health independently of their role in pigment formation“, explains Sarita Hebbar, one of the lead authors of the study.

To find this out, the scientists investigated different mutations of the fruit fly Drosophila melanogaster using a combination of genetics, altered diet and biochemical analysis of the products of the kynurenine metabolic pathway. Sofia Traikov, one of the co-authors, developed a method for detecting and quantifying these metabolic products. This enabled the researchers to establish a link between the health status of the retina and the concentration of various metabolites.

They found that one metabolite that damages the retina is 3-hydroxykynurenine (3OH-K). More importantly, they were able to show that the degree of degeneration is influenced by the ratio between the toxic 3OH-K and protective metabolites such as kynurenic acid (KYNA), and not just by their absolute amount. Sarita adds: „We also fed two of these metabolites to normal (non-mutant) flies and found that 3OH-K enhances stress-induced retinal damage, while KYNA protects the retina from stress-induced damage.This means that under certain conditions, retinal health can be improved by altering the ratio of KP metabolites.

In addition, by specifically influencing these four genes and thus the four different steps within the metabolic pathway, the researchers were able to show that not only the accumulation of 3OH-K itself, but also its retention in certain cell compartments or organelles and thus its availability for further reactions are important for the health of the retina.

„This work shows that the kynurenine metabolic pathway is not only important for the colour of the fly eye, but that its metabolites are important for the regulation of cellular functions and thus for the health of the cells,

says Elisabeth Knust, who led the study. She concludes: „For future therapies targeting diseases with impaired function of the kynurenine pathway, such as those observed in various neurodegenerative diseases, the relationship between the different metabolites and the specific sites where they accumulate, as well as their activity, must be taken into account.“

Article from the "Max Planck Society" from 23 March 2023