A recent study published in PLOS Genetics evaluated the role of the kynurenine pathway (KP) in retinal homeostasis using light stress in flies as a model system.
Give me some background.
The kynurenine pathway converts the amino acid tryptophan into various metabolites, including kynurenine (K) and 3-hydroxykynurenine (3OH-K), which have both been associated with degenerative conditions in animal models and human disease tissues.
Disruption of this metabolic pathway can result in the buildup of either toxic or protective metabolites. As a result, the KP is currently of interest to researchers as a therapeutic target for neurological disorders.
Talk about the study.
Using the Drosophila melanogaster genes cinnabar, cardinal, white, and scarlet, investigators decoupled the role of these genes in regulating eye color pigmentation from how they encode different steps in the kynurenine pathway.
By employing a combination of genetic analyses, dietary changes, and biochemical analyses of metabolites to study the impact of mutations of these genes, researchers assessed the influence of individual metabolites from the KP on retinal health—independent of their role in pigment formation.
Results?
Using white as a sensitized genetic background, researchers showed that mutations in cinnabar, cardinal, and scarlet differentially modulate light-induced retinal damage.
Mass spectrometric measurements of KP metabolites showed that increased levels of 3OH-K and xanthurenic acid induced further tissue damage, while K and kynurenic acid (KYNA) had neuroprotective effects.
Tell me more.
The study also noted that the degree of degeneration was influenced by the balance between toxic (3OH-K) and protective (KYNA) metabolites—not simply by their absolute amounts.
Further, 3OH-K lost toxicity when in its protein-bound form (PB-3OH-K), worsening light-induced retinal degeneration as a free molecule.
How did they verify this?
Researchers corroborated these results by feeding 3OH-K and KYNA to non-mutant flies ; which they noted that, respectively, resulting in an amplification of stress-induced retinal damage and protection of the retina in sensitized genetic backgrounds.
Significance?
The results of this study provide potential avenues for regulating retinal homeostasis and treating neurodegenerative diseases using metabolites from the kynurenine pathway, or their compartmentalization, for disease alleviation.
Specifically, isolating 3OH-K either in protein-bound form or with compartmentalization offers a mechanism to mitigate its toxicity and role in neurodegeneration.