ENVISIONING INTERVENTION

The work, presented in a paper published in 2015 [Rice DS, et al. Nat Commun. 2015 Mar 4;6:6228], comprised a series of experiments involving a genetically modified mouse model developed by Dr Bazan and colleagues, cultures of human RPE cells, in situ hybridization analysis and other state-of-the art techniques. The findings established adiponectin receptor 1 (AdipoR1) as a regulatory switch mediating docosahexaenoic acid (DHA) uptake, retention, conservation and elongation in photoreceptor and RPE cells, and thus, a role for AdipoR1 in preserving photoreceptor integrity and survival.

“As a receptor for the hormone adiponectin, AdipoR1 is known to have a critical role in obesity and diseases including metabolic syndrome, cancer, and many others. Now, we have described a novel function of this integral membrane protein, showing that it selectively and specifically controls the DHA lipidome in RPE and photoreceptor cells,” said Dr Bazan, Boyd Professor and Director, Louisiana State University Health New Orleans Neuroscience Center of Excellence, New Orleans, USA.

“Knowing that the photoreceptor DHA lipidome comprises endogenous cell survival responses, we believe the AdipoR1 regulatory switch may be harnessed in the near future to develop new therapies for retinal degenerative diseases.”

LATENCY PERIOD

Recognising that there is a latency period to manifestation of retinitis pigmentosa and other inheritable retinal degenerative diseases, Dr. Bazan said there may be cell-specific responses that counteract the consequences of mutation expression, gene susceptibility, and/or the onset of uncompensated oxidative stress. Uncovering these mechanisms would provide a foundation for targeted design of therapeutic modalities that could be used for early intervention to delay the eventual onset of disease and/or its early progression.

Dr Bazan explained that DHA, a dietary-derived essential fatty acid, is avidly retained and enriched in the central nervous system, where it is found at its highest concentration in photoreceptor cells. In addition, accumulating evidence supported its importance for photoreceptor function and in retinal degenerative diseases. However, the molecular mechanisms governing the uptake and retention of DHA by photoreceptor and RPE cells remained unknown.

Previous research had also established the presence of high levels of AdipoR1 in the RPE and neural retina, but its function was unknown as well.

Studying an AdipoR1 knockout mouse, Dr Bazan and colleagues found these animals developed a flecked retina and evidence of functional demise prior with attenuated electroretinograms, prolonged dark recovery, and an impaired retinol visual cycle prior to photoreceptor degeneration. However, knockout mice lacking adiponectin, the cognate ligand of AdipoR1, did not display the retinal degeneration phenotype.

Mice lacking AdipoR1 also exhibited reduced retinal levels of DHA, which was shown to be the result of reduced retinal uptake through ex vivo studies where explants of eyecups/RPE from the AdipoR1 KO mice were cultured with labelled DHA. The retinas of AdipoR1 knockout mice also lacked phosphatidyl choline molecular species with very long chain polyunsaturated fatty acids (VLC-PUFAs). Instead, minor VLC-PUFAs not containing DHA were formed, perhaps as a compensatory response, the investigators hypothesised.

A role of AdipoR1 for DHA uptake by human RPE cells was also established by incubating the cells with labelled DHA. The results showed DHA uptake was increased when cells overexpressed AdipoR1 but was decreased with silencing of the receptor.

Dr Bazan said that dietary supplementation with omega-3 fatty acids is probably not the answer by itself. He believes there are specific requirements for omega-3 fatty acids for photoreceptor function that are liver dependent.