Molecules and Cells

  • 제46권11호
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  • Pages.675-687
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  • 2023
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  • 1016-8478(pISSN)
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  • 0219-1032(eISSN)
한국분자세포생물학회 (Korean Society for Molecular and Cellular Biology)
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Activation of Lysosomal Function Ameliorates Amyloid-β-Induced Tight Junction Disruption in the Retinal Pigment Epithelium

  • Dong Hyun Jo (Department of Anatomy and Cell Biology, Seoul National University College of Medicine) ;
  • Su Hyun Lee (Department of Biochemistry and Molecular Biology, Korea University College of Medicine) ;
  • Minsol Jeon (Department of Biochemistry and Molecular Biology, Korea University College of Medicine) ;
  • Chang Sik Cho (Fight against Angiogenesis-Related Blindness (FARB) Laboratory, Biomedical Research Institute, Seoul National University Hospital) ;
  • Da-Eun Kim (Department of Biochemistry and Molecular Biology, Korea University College of Medicine) ;
  • Hyunkyung Kim (Department of Biochemistry and Molecular Biology, Korea University College of Medicine) ;
  • Jeong Hun Kim (Fight against Angiogenesis-Related Blindness (FARB) Laboratory, Biomedical Research Institute, Seoul National University Hospital)
  • 투고 : 2023.04.07
  • 심사 : 2023.10.17
  • 발행 : 2023.11.30
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초록

Accumulation of pathogenic amyloid-β disrupts the tight junction of retinal pigment epithelium (RPE), one of its senescence-like structural alterations. In the clearance of amyloid-β, the autophagy-lysosome pathway plays the crucial role. In this context, mammalian target of rapamycin (mTOR) inhibits the process of autophagy and lysosomal degradation, acting as a potential therapeutic target for age-associated disorders. However, efficacy of targeting mTOR to treat age-related macular degeneration remains largely elusive. Here, we validated the therapeutic efficacy of the mTOR inhibitors, Torin and PP242, in clearing amyloid-β by inducing the autophagy-lysosome pathway in a mouse model with pathogenic amyloid-β with tight junction disruption of RPE, which is evident in dry age-related macular degeneration. High concentration of amyloid-β oligomers induced autophagy-lysosome pathway impairment accompanied by the accumulation of p62 and decreased lysosomal activity in RPE cells. However, Torin and PP242 treatment restored the lysosomal activity via activation of LAMP2 and facilitated the clearance of amyloid-β in vitro and in vivo. Furthermore, clearance of amyloid-β by Torin and PP242 ameliorated the tight junction disruption of RPE in vivo. Overall, our findings suggest mTOR inhibition as a new therapeutic strategy for the restoration of tight junctions in age-related macular degeneration.

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과제정보

This study was supported by the Basic Science Research Program (NRF-2022R1A2C2010940 to H.K. and NRF-2022R1A2C1003768, NRF-2023M3A9I4009901 to D.H.J.), the Creative Materials Discovery Program (NRF-2018M3D1A1058826 to J.H.K.) from the National Research Foundation (NRF) of Korea funded by the Korean government, the Korea Research Institute of Bioscience and Biotechnology (KRIBB) Research Initiative Program (KGM5362111 to J.H.K.), the Ministry of Trade, Industry, and Energy, and the Ministry of Health and Welfare (HN21C0917 to J.H.K.), Kun-hee Lee Child Cancer & Rare Disease Project, Republic of Korea (202200004004 to J.H.K.), Seoul National University Hospital Research Grant (18-2023-0010 to J.H.K.), and the Bio & Medical Technology Program of the NRF funded by the Korean government, MSIP (NRF-2022M3A9E4017127 to J.H.K.).

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