Disrupted cholesterol metabolism promotes age-related photoreceptor neurodegeneration

• Published in: Journal of lipid research Vol. 59; no. 8; pp. 1414 - 1423
• Main Authors: Ban, Norimitsu, Lee, Tae Jun, Sene, Abdoulaye, Dong, Zhenyu, Santeford, Andrea, Lin, Jonathan B., Ory, Daniel S., Apte, Rajendra S.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-08-2018; Journal of Lipid Research; The American Society for Biochemistry and Molecular Biology; Elsevier
• Subjects: ABCA1 protein; Age; aging; Aging - metabolism; Aging - pathology; Aging - physiology; Animals; ATP Binding Cassette Transporter 1 - deficiency; ATP Binding Cassette Transporter 1 - genetics; ATP binding cassette transporter G1; ATP Binding Cassette Transporter, Subfamily G, Member 1 - deficiency; ATP Binding Cassette Transporter, Subfamily G, Member 1 - genetics; ATP-binding protein; Blindness; Cell membranes; Cholesterol; Cholesterol - metabolism; cholesterol/dietary; cholesterol/efflux; Circadian rhythms; Clonal deletion; eye/retina; Gene Deletion; High fat diet; Homeostasis; Lipid membranes; Lipid metabolism; Metabolism; Metabolites; Mice; Neurodegeneration; neurons; Photoreceptors; Retina; Retinal Cone Photoreceptor Cells - metabolism; Retinal Cone Photoreceptor Cells - pathology; Retinal degeneration; Retinal Rod Photoreceptor Cells - metabolism; Retinal Rod Photoreceptor Cells - pathology; Rod outer segment membranes; Vision, Ocular; eye/retina; aging; cholesterol/dietary; neurons; cholesterol/efflux; ATP binding cassette transporter G1
• ISSN: 0022-2275; 1539-7262
• DOI: 10.1194/jlr.M084442

Photoreceptors have high intrinsic metabolic demand and are exquisitely sensitive to metabolic perturbation. In addition, they shed a large portion of their outer segment lipid membranes in a circadian manner, increasing the metabolic burden on the outer retina associated with the resynthesis of cell membranes and disposal of the cellular cargo. Here, we demonstrate that deletion of both ABCA1 and ABCG1 in rod photoreceptors leads to age-related accumulation of cholesterol metabolites in the outer retina, photoreceptor dysfunction, degeneration of rod outer segments, and ultimately blindness. A high-fat diet significantly accelerates rod neurodegeneration and vision loss, further highlighting the role of lipid homeostasis in regulating photoreceptor neurodegeneration and vision.