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

Jessica D. Rosarda, Sarah Giles, Sarah Harkins-Perry, Elizabeth A. Mills, Martin Friedlander, R. Luke Wiseman and Kevin T. Eade ()
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Jessica D. Rosarda: The Scripps Research Institute
Sarah Giles: The Scripps Research Institute
Sarah Harkins-Perry: The Scripps Research Institute
Elizabeth A. Mills: The Scripps Research Institute
Martin Friedlander: The Scripps Research Institute
R. Luke Wiseman: The Scripps Research Institute
Kevin T. Eade: The Scripps Research Institute

Nature Communications, 2023, vol. 14, issue 1, 1-13

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-39775-w

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