Inhibition of ceramide accumulation in AdipoR1–/– mice increases photoreceptor survival and improves vision

• DOI: 10.1172/jci.insight.156301
• Publication Date: 2022-01-11T18:11:30Z
• Authors: Dominik Lewandowski; Andrzej T. Foik; Roman Smidak; Elliot H. Choi; Jianye Zhang; Thanh Hoang; Aleksander Tworak; Susie Suh; Henri Leinonen; Zhiqian Dong; Antonio F.M. Pinto; Emily Tom; Jennings Luu; Joan Lee; Xiuli Ma; Erhard Bieberich; Seth Blackshaw; Alan Saghatelian; David C. Lyon; Dorota Skowronska...; Marcin Tabaka; Krzysztof Palczewski
• Keywords: 0301 basic medicine; 570; DNA Mutational Analysis; 610; Eye; Inbred C57BL; Mice; 03 medical and health sciences; Rare Diseases; Retinal Diseases; Receptors; Ceramidases; Animals; Eye Disease and Disorders of Vision; Animal; Neurosciences; R; DNA; Mice, Mutant Strains; 3. Good health; Mutant Strains; Mice, Inbred C57BL; Ophthalmology; Disease Models, Animal; Disease Models; Mutation; Retinal Cone Photoreceptor Cells; Medicine; Adiponectin; Drug therapy; Receptors, Adiponectin; Research Article

Adiponectin receptor 1 (ADIPOR1) is a lipid and glucose metabolism regulator that possesses intrinsic ceramidase activity. Mutations of the ADIPOR1 gene have been associated with nonsyndromic syndromic retinitis pigmentosa. Here, we show absence AdipoR1 in mice leads to progressive photoreceptor degeneration, significant reduction electroretinogram amplitudes, decreased retinoid content retina, reduced cone opsin expression. Single-cell RNA-Seq results indicate encoded most abundantly expressed one 2 highly ceramidases human next acid ASAH1. We discovered an accumulation ceramides AdipoR1-/- likely due insufficient activity for healthy retina function, resulting death. Combined treatment desipramine/L-cycloserine (DC) lowered ceramide levels exerted protective effect on photoreceptors mice. Moreover, observed improvement cone-mediated retinal function DC-treated animals. Lastly, found prolonged DC corrected electrical responses primary visual cortex stimuli, approaching near-normal some parameters. These highlight importance pharmacological inhibition generation can provide therapeutic strategy ADIPOR1-related retinopathy.