ArticleNature communications2023
Imbalanced unfolded protein response signaling contributes to 1-deoxysphingolipid retinal toxicity.
Article in Nature communications, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
What it found
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The trial behind it
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Who cites it
15 citing papers in PubMed, 30 citations in OpenAlex.
- Macular telangiectasia type 2: An update.The Journal of international medical research · 2026Review
- 1-deoxysphingolipids dysregulate membrane properties and cargo trafficking in the early secretory pathway.Cell chemical biology · 2026Article
- Very long-chain fatty acids drive 1-deoxySphingolipid toxicity.Nature communications · 2025Article
- Diabetes mellitus and the key role of endoplasmic reticulum stress in pancreatic β cells.Nature reviews. Endocrinology · 2025Review
- Article
- Diabetic retinopathy and Alzheimer's disease: Convergence of the unfolded protein response in neurodegeneration.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2025Review
- Article
- The role of 1-Deoxysphingolipids and Polyamines in the pathogenesis of placental syndrome.BMC pregnancy and childbirth · 2025Article
- Genetic Background of Macular Telangiectasia Type 2.International journal of molecular sciences · 2025Review
- Organoids: their emerging essential role in pathological mechanisms and drug discovery of diabetes and its complications.Frontiers in pharmacology · 2025Review
- Regulation of cellular and systemic sphingolipid homeostasis.Nature reviews. Molecular cell biology · 2024Review
- Enzymes of sphingolipid metabolism as transducers of metabolic inputs.Biochemical Society transactions · 2024Review
- Mapping stress-responsive signaling pathways induced by mitochondrial proteostasis perturbations.Molecular biology of the cell · 2024Article
- Mapping Stress-Responsive Signaling Pathways Induced by Mitochondrial Proteostasis Perturbations.bioRxiv : the preprint server for biology · 2024Article
- The endoplasmic reticulum: Homeostasis and crosstalk in retinal health and disease.Progress in retinal and eye research · 2024Review
Corrections and comments
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Authors and funding
7 authors at 1 institution in 1 country.
Funding
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.