A new study by researchers at the University of Eastern Finland (UEF) reports changes in the dopamine system of the retina during inherited retinal degeneration. Inherited retinal degenerations form a diverse group of genetic eye diseases that lead to vision impairment and blindness as retinal function progressively declines. The study, published in the Journal of Neurochemistry, examined changes in the retinal dopamine system using mouse models of two forms of the disease.
Retinal dopamine levels rise in inherited retinal degeneration
Researchers found that retinal dopamine concentrations increase in the tissue even before structural degeneration begins and remain elevated as the disease progresses. The study further revealed changes in dopamine metabolism and in the expression of genes related to the broader catecholamine system compared with healthy retinas.
For the first time, the study also measured and localised dopamine in the mouse retina using matrix-assisted laser desorption/ionisation mass spectrometry imaging, in collaboration with researchers from Uppsala University.
Dopamine is a catecholamine neurotransmitter important for normal retinal development and function, but its role in retinal degeneration remains unclear. It acts throughout the tissue, and its effects differ between retinal cell types. Although the current study does not establish a causal link between increased dopamine levels and disease progression, the results suggest overactivation of the dopamine system during retinal degeneration and warrant further research.
Towards a treatment that works regardless of the mutation
Hundreds of different gene mutations can cause inherited retinal degeneration, which makes the development of gene therapies challenging from both an economic and a scientific perspective. The research group led by Associate Professor Henri Leinonen at the UEF School of Pharmacy is developing a combination treatment that targets dopamine and the wider catecholamine system, and that could be used in different forms of retinal degeneration regardless of the underlying mutation. The concept builds on animal studies in which compounds acting on the catecholamine system, such as alpha-2 adrenergic agonists and dopamine D2 receptor agonists, have slowed the progression of retinal degeneration.
“We know that retinal degeneration can be slowed in animal models by targeting the catecholamine system. However, we do not know why. The field is very fragmented: different laboratories have discovered promising individual compounds, but there is no unifying explanation for how they work. Our results are one piece of this puzzle. I am confident that the mechanism will be found, as long as the research continues,” says Leinonen.
Next, the group will assess what the increased dopamine concentration means for disease progression: does it accelerate degeneration, protect against it, or is it simply a by-product of other changes in the degenerating retina? Regardless of the answer, the study shows that the catecholamine system is altered early and consistently across two genetically distinct disease models, which strengthens the rationale for targeting it.
Research article: https://onlinelibrary.wiley.com/doi/10.1111/jnc.70552
