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Updated: Jul 23, 2025
Toxicity Screens in Human Retinal Organoids for Pharmaceutical Discovery
Published on: March 4, 2021
Imbalanced unfolded protein response signaling contributes to 1-deoxysphingolipid retinal toxicity
Jessica D Rosarda1, Sarah Giles1,2, Sarah Harkins-Perry1,2
1Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, 92037, USA.
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.
Insights
Cytotoxic 1-deoxysphingolipids (1-dSLs) cause retinal cell damage. Targeting the unfolded protein response (UPR) pathways, specifically activating ATF6, can mitigate this toxicity, offering new therapeutic avenues for related eye diseases.
Area of Science:
- Cellular biology
- Molecular ophthalmology
- Retinal disease mechanisms
Background:
- Atypical cytotoxic 1-deoxysphingolipids (1-dSLs) are linked to retinal diseases like diabetic retinopathy and Macular Telangiectasia Type 2.
- The precise molecular mechanisms of 1-dSL-induced retinal cell toxicity are not fully understood.
Purpose of the Study:
- To elucidate the biological pathways modulating 1-dSL toxicity in human retinal organoids.
- To identify potential therapeutic targets for 1-dSL-associated retinal pathologies.
Main Methods:
- Integration of bulk and single-nucleus RNA-sequencing in human retinal organoids.
- Pharmacologic manipulation of unfolded protein response (UPR) signaling pathways (PERK, ATF6).
Main Results:
- 1-dSLs differentially activate UPR signaling arms in photoreceptor cells and Müller glia.
- Sustained PERK signaling (integrated stress response) and ATF6 deficiencies contribute to 1-dSL photoreceptor toxicity.
- Pharmacologic activation of ATF6 effectively reduces 1-dSL toxicity without affecting PERK/ISR signaling.
Conclusions:
- Specific arms of the UPR play distinct roles in 1-dSL-induced retinal toxicity.
- Targeting the ATF6 arm of the UPR presents a promising therapeutic strategy for 1-dSL-related retinal diseases.
- This study reveals novel intervention points for treating diseases linked to 1-dSL accumulation.
Related Concept Videos
01:31Regulation of the Unfolded Protein Response
01:37The Unfolded Protein Response