Abstract
Purpose :
ELOVL2 (Elongation Of Very Long Chain Fatty Acids-Like 2) encodes a transmembrane protein involved in the synthesis of very long polyunsaturated fatty acids (VLC-PUFAs) and is highly expressed in neuronal tissues including retina. Recent studies indicate that DNA methylation status of the ELOVL2 regulatory region predicts human chronological age. The correlation between the methylation status of the Elovl2 regulatory region and age has been validated in mice. However, the molecular role of ELOVL2 in aging has never been investigated. Understanding the role of ELOVL2 may be particularly important in the retina as VLC-PUFAs play a critical role in retinal biology (e.g., building highly curved membranes in photoreceptor outer segment discs), vision, and photoreceptor renewal, which are key processes that are impacted in age-related vision decline. We investigated the role of Elongation Of Very Long Chain Fatty Acids-Like 2 (ELOVL2) gene in the pathogenesis of age-related macular degeneration.
Methods :
We analyzed methylation of regulatory elements and expression of Elovl2 gene in aging mouse retina and correlated it with the visual functions by electroretinogram (ERG). We generated mutant animals to investigate how the ablation of the enzymatic activity of Elovl2 affects aging of the eye including histological and functional changes in the retina.
Results :
We show that expression of Elovl2 is gradually declining with the age of mice what is followed by decline of visual functions as measured by ERG. This change has been also correlated with the increase of DNA methylation of Elovl2 regulatory elements. Further, drug-directed demethylation of the regulatory element of Elovl2 is sufficient to induce its expression and improve visual functions. Finally, mice lacking Elovl2 enzymatic function exhibit accelerated vision decline and development of drusen-like deposits in the retina reminiscent of symptoms of dry age-related macular degeneration.
Conclusions :
We conclude that Elovl2 plays an important role in retinal health and that loss of the Elovl2 expression may represent one of the first signs of retinal aging and disease. Importantly, our Elovl2 mutant mice might be helpful in studying the mechanism of dry age-related macular degeneration.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.