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The AKT2/SIRT5/TFEB pathway as a potential therapeutic target in non-neovascular AMD.
Ghosh, Sayan; Sharma, Ruchi; Bammidi, Sridhar; Koontz, Victoria; Nemani, Mihir; Yazdankhah, Meysam; Kedziora, Katarzyna M; Stolz, Donna Beer; Wallace, Callen T; Yu-Wei, Cheng; Franks, Jonathan; Bose, Devika; Shang, Peng; Ambrosino, Helena M; Dutton, James R; Geng, Zhaohui; Montford, Jair; Ryu, Jiwon; Rajasundaram, Dhivyaa; Hose, Stacey; Sahel, José-Alain; Puertollano, Rosa; Finkel, Toren; Zigler, J Samuel; Sergeev, Yuri; Watkins, Simon C; Goetzman, Eric S; Ferrington, Deborah A; Flores-Bellver, Miguel; Kaarniranta, Kai; Sodhi, Akrit; Bharti, Kapil; Handa, James T; Sinha, Debasish.
Affiliation
  • Ghosh S; Department of Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
  • Sharma R; Ocular and Stem Cell Translational Research Section, National Eye Institute, National Institutes of Health, Bethesda, MD, USA.
  • Bammidi S; Department of Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
  • Koontz V; Department of Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
  • Nemani M; Department of Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
  • Yazdankhah M; Department of Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
  • Kedziora KM; Department of Cell Biology, Center for Biologic Imaging, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
  • Stolz DB; Department of Cell Biology, Center for Biologic Imaging, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
  • Wallace CT; Department of Cell Biology, Center for Biologic Imaging, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
  • Yu-Wei C; Aging Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
  • Franks J; Department of Cell Biology, Center for Biologic Imaging, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
  • Bose D; Ocular and Stem Cell Translational Research Section, National Eye Institute, National Institutes of Health, Bethesda, MD, USA.
  • Shang P; Doheny Eye Institute, Pasadena, CA, USA.
  • Ambrosino HM; Doheny Eye Institute, Pasadena, CA, USA.
  • Dutton JR; Stem Cell Institute, University of Minnesota, Minneapolis, MN, USA.
  • Geng Z; Stem Cell Institute, University of Minnesota, Minneapolis, MN, USA.
  • Montford J; Ocular and Stem Cell Translational Research Section, National Eye Institute, National Institutes of Health, Bethesda, MD, USA.
  • Ryu J; Ocular and Stem Cell Translational Research Section, National Eye Institute, National Institutes of Health, Bethesda, MD, USA.
  • Rajasundaram D; Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
  • Hose S; Department of Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
  • Sahel JA; Department of Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
  • Puertollano R; Institut De La Vision, INSERM, CNRS, Sorbonne Université, Paris, France.
  • Finkel T; Cell Biology and Physiology Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
  • Zigler JS; Aging Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
  • Sergeev Y; Wilmer Eye Institute, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • Watkins SC; Protein Biochemistry & Molecular Modeling Group, National Eye Institute, National Institutes of Health, Bethesda, MD, USA.
  • Goetzman ES; Department of Cell Biology, Center for Biologic Imaging, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
  • Ferrington DA; Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
  • Flores-Bellver M; Doheny Eye Institute, Pasadena, CA, USA.
  • Kaarniranta K; Department of Ophthalmology, University of California Los Angeles, Los Angeles, CA, USA.
  • Sodhi A; Department of Ophthalmology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
  • Bharti K; Department of Ophthalmology, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland.
  • Handa JT; Department of Molecular Genetics, University of Lodz, Lodz, Poland.
  • Sinha D; Wilmer Eye Institute, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Nat Commun ; 15(1): 6150, 2024 Jul 21.
Article in En | MEDLINE | ID: mdl-39034314
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.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Autophagy / Signal Transduction / Sirtuins / Proto-Oncogene Proteins c-akt / Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Retinal Pigment Epithelium / Lysosomes / Macular Degeneration Limits: Animals / Humans / Male Language: En Journal: Nat Commun Year: 2024 Document type: Article
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Autophagy / Signal Transduction / Sirtuins / Proto-Oncogene Proteins c-akt / Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Retinal Pigment Epithelium / Lysosomes / Macular Degeneration Limits: Animals / Humans / Male Language: En Journal: Nat Commun Year: 2024 Document type: Article