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Imbalanced unfolded protein response signaling contributes to 1-deoxysphingolipid retinal toxicity

Author

Listed:
  • Jessica D. Rosarda

    (The Scripps Research Institute)

  • Sarah Giles

    (The Scripps Research Institute
    Lowy Medical Research Institute)

  • Sarah Harkins-Perry

    (The Scripps Research Institute
    Lowy Medical Research Institute)

  • Elizabeth A. Mills

    (The Scripps Research Institute
    Lowy Medical Research Institute)

  • Martin Friedlander

    (The Scripps Research Institute
    Lowy Medical Research Institute)

  • R. Luke Wiseman

    (The Scripps Research Institute)

  • Kevin T. Eade

    (The Scripps Research Institute
    Lowy Medical Research Institute)

Abstract

The accumulation of atypical, cytotoxic 1-deoxysphingolipids (1-dSLs) has been linked to retinal diseases such as diabetic retinopathy and Macular Telangiectasia Type 2. However, the molecular mechanisms by which 1-dSLs induce toxicity in retinal cells remain poorly understood. Here, we integrate bulk and single-nucleus RNA-sequencing to define biological pathways that modulate 1-dSL toxicity in human retinal organoids. Our results demonstrate that 1-dSLs differentially activate signaling arms of the unfolded protein response (UPR) in photoreceptor cells and Müller glia. Using a combination of pharmacologic activators and inhibitors, we show that sustained PERK signaling through the integrated stress response (ISR) and deficiencies in signaling through the protective ATF6 arm of the UPR are implicated in 1-dSL-induced photoreceptor toxicity. Further, we demonstrate that pharmacologic activation of ATF6 mitigates 1-dSL toxicity without impacting PERK/ISR signaling. Collectively, our results identify new opportunities to intervene in 1-dSL linked diseases through targeting different arms of the UPR.

Suggested Citation

  • Jessica D. Rosarda & Sarah Giles & Sarah Harkins-Perry & Elizabeth A. Mills & Martin Friedlander & R. Luke Wiseman & Kevin T. Eade, 2023. "Imbalanced unfolded protein response signaling contributes to 1-deoxysphingolipid retinal toxicity," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-39775-w
    DOI: 10.1038/s41467-023-39775-w
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    1. Mototsugu Eiraku & Nozomu Takata & Hiroki Ishibashi & Masako Kawada & Eriko Sakakura & Satoru Okuda & Kiyotoshi Sekiguchi & Taiji Adachi & Yoshiki Sasai, 2011. "Self-organizing optic-cup morphogenesis in three-dimensional culture," Nature, Nature, vol. 472(7341), pages 51-56, April.
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