1. The AKT2/SIRT5/TFEB pathway as a potential therapeutic target in non-neovascular AMD.
- Author
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Ghosh S, Sharma R, Bammidi S, Koontz V, Nemani M, Yazdankhah M, Kedziora KM, Stolz DB, Wallace CT, Yu-Wei C, Franks J, Bose D, Shang P, Ambrosino HM, Dutton JR, Geng Z, Montford J, Ryu J, Rajasundaram D, Hose S, Sahel JA, Puertollano R, Finkel T, Zigler JS Jr, Sergeev Y, Watkins SC, Goetzman ES, Ferrington DA, Flores-Bellver M, Kaarniranta K, Sodhi A, Bharti K, Handa JT, and Sinha D
- Subjects
- Animals, Humans, Mice, Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha metabolism, Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha genetics, Mice, Inbred C57BL, Mitochondria metabolism, Disease Models, Animal, Induced Pluripotent Stem Cells metabolism, Male, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors metabolism, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors genetics, Proto-Oncogene Proteins c-akt metabolism, Sirtuins metabolism, Sirtuins genetics, Macular Degeneration metabolism, Macular Degeneration pathology, Macular Degeneration genetics, Retinal Pigment Epithelium metabolism, Retinal Pigment Epithelium pathology, Lysosomes metabolism, Signal Transduction, Autophagy
- Abstract
Non-neovascular or dry age-related macular degeneration (AMD) is a multi-factorial disease with degeneration of the aging retinal-pigmented epithelium (RPE). Lysosomes play a crucial role in RPE health via phagocytosis and autophagy, which are regulated by transcription factor EB/E3 (TFEB/E3). Here, we find that increased AKT2 inhibits PGC-1α to downregulate SIRT5, which we identify as an AKT2 binding partner. Crosstalk between SIRT5 and AKT2 facilitates TFEB-dependent lysosomal function in the RPE. AKT2/SIRT5/TFEB pathway inhibition in the RPE induced lysosome/autophagy signaling abnormalities, disrupted mitochondrial function and induced release of debris contributing to drusen. Accordingly, AKT2 overexpression in the RPE caused a dry AMD-like phenotype in aging Akt2 KI mice, as evident from decline in retinal function. Importantly, we show that induced pluripotent stem cell-derived RPE encoding the major risk variant associated with AMD (complement factor H; CFH Y402H) express increased AKT2, impairing TFEB/TFE3-dependent lysosomal function. Collectively, these findings suggest that targeting the AKT2/SIRT5/TFEB pathway may be an effective therapy to delay the progression of dry AMD., (© 2024. The Author(s).)
- Published
- 2024
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