UMMS Affiliation

Department of Ophthalmology and Visual Sciences

Publication Date

2020-06-09

Document Type

Article

Disciplines

Biochemical Phenomena, Metabolism, and Nutrition | Eye Diseases | Neuroscience and Neurobiology | Ophthalmology | Pathological Conditions, Signs and Symptoms

Abstract

Age-related macular degeneration (AMD) is the leading cause of blindness in the elderly. While the histopathology of the different disease stages is well characterized, the cause underlying the progression, from the early drusen stage to the advanced macular degeneration stage that leads to blindness, remains unknown. Here, we show that photoreceptors (PRs) of diseased individuals display increased expression of two key glycolytic genes, suggestive of a glucose shortage during disease. Mimicking aspects of this metabolic profile in PRs of wild-type mice by activation of the mammalian target of rapamycin complex 1 (mTORC1) caused early drusen-like pathologies, as well as advanced AMD-like pathologies. Mice with activated mTORC1 in PRs also displayed other early disease features, such as a delay in photoreceptor outer segment (POS) clearance and accumulation of lipofuscin in the retinal-pigmented epithelium (RPE) and of lipoproteins at the Bruch's membrane (BrM), as well as changes in complement accumulation. Interestingly, formation of drusen-like deposits was dependent on activation of mTORC1 in cones. Both major types of advanced AMD pathologies, including geographic atrophy (GA) and neovascular pathologies, were also seen. Finally, activated mTORC1 in PRs resulted in a threefold reduction in di-docosahexaenoic acid (DHA)-containing phospholipid species. Feeding mice a DHA-enriched diet alleviated most pathologies. The data recapitulate many aspects of the human disease, suggesting that metabolic adaptations in photoreceptors could contribute to disease progression in AMD. Identifying the changes downstream of mTORC1 that lead to advanced pathologies in mouse might present new opportunities to study the role of PRs in AMD pathogenesis.

Keywords

AMD, geographic atrophy, photoreceptor metabolism, photoreceptors, wet AMD

Rights and Permissions

Copyright © 2020 the Author(s). Published by PNAS. This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND).

DOI of Published Version

10.1073/pnas.2000339117

Source

Cheng SY, Cipi J, Ma S, Hafler BP, Kanadia RN, Brush RS, Agbaga MP, Punzo C. Altered photoreceptor metabolism in mouse causes late stage age-related macular degeneration-like pathologies. Proc Natl Acad Sci U S A. 2020 Jun 9;117(23):13094-13104. doi: 10.1073/pnas.2000339117. Epub 2020 May 20. PMID: 32434914; PMCID: PMC7293639. Link to article on publisher's site

Journal/Book/Conference Title

Proceedings of the National Academy of Sciences of the United States of America

Related Resources

Link to Article in PubMed

PubMed ID

32434914

Creative Commons License

Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.

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