Altered photoreceptor metabolism in mouse causes late stage age-related macular degeneration-like pathologies

被引:65
作者
Cheng, Shun-Yun [1 ]
Cipi, Joris [1 ]
Ma, Shan [1 ]
Hafler, Brian P. [2 ,3 ]
Kanadia, Rahul N. [4 ]
Brush, Richard S. [5 ,6 ,7 ,8 ]
Agbaga, Martin-Paul [5 ,6 ,7 ,8 ]
Punzo, Claudio [1 ]
机构
[1] Univ Massachusetts, Med Sch, Dept Ophthalmol & Visual Sci, Worcester, MA 01655 USA
[2] Yale Sch Med, Dept Ophthalmol & Visual Sci, New Haven, CT 06510 USA
[3] Yale Sch Med, Dept Pathol, New Haven, CT 06510 USA
[4] Univ Connecticut, Dept Physiol & Neurobiol, Storrs, CT 06269 USA
[5] Univ Oklahoma, Hlth Sci Ctr, Dept Cell Biol, Oklahoma City, OK 73104 USA
[6] Univ Oklahoma, Hlth Sci Ctr, Dept Ophthalmol, Oklahoma City, OK 73104 USA
[7] Univ Oklahoma, Hlth Sci Ctr, Harold Hamm Diabet Ctr, Oklahoma City, OK 73104 USA
[8] Univ Oklahoma, Hlth Sci Ctr, Dean A McGee Eye Inst, Oklahoma City, OK 73104 USA
关键词
AMD; photoreceptors; geographic atrophy; wet AMD; photoreceptor; metabolism; PIGMENT EPITHELIAL-CELLS; GEOGRAPHIC ATROPHY; AEROBIC GLYCOLYSIS; FATTY-ACIDS; CONE DEATH; MTOR; OMEGA-3-FATTY-ACIDS; TRANSLOCATION; RECURRENCE; SIROLIMUS;
D O I
10.1073/pnas.2000339117
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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 pro-gression, 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, sugges-tive 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 pa-thologies. Mice with activated mTORC1 in PRs also displayed other early disease features, such as a delay in photoreceptor outer seg-ment (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 neovas-cular 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 as-pects 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 ad-vanced pathologies in mouse might present new opportunities to study the role of PRs in AMD pathogenesis.
引用
收藏
页码:13094 / 13104
页数:11
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