The chemical chaperone 4-phenylbutyric acid rescues molecular cell defects of COL3A1 mutations that cause vascular Ehlers Danlos Syndrome
Abstract Vascular Ehlers Danlos Syndrome (vEDS) is a connective tissue disorder caused by COL3A1 mutations for which there are no treatments due to a limited understanding of underlying mechanisms. We aimed to identify the molecular insults of mutations, focusing on collagen folding, to establish if...
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Nature Publishing Group
2025-04-01
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| Series: | Cell Death Discovery |
| Online Access: | https://doi.org/10.1038/s41420-025-02476-y |
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| author | Ramla Omar Michelle AW Lee Laura Gonzalez-Trueba Cameron R. Thomson Uwe Hansen Spyridonas Lianos Snoopy Hazarika Omar HMEH El Abdallah Malak A. Ammar Jennifer Cassels Alison M. Michie Neil J. Bulleid Fransiska Malfait Tom Van Agtmael |
| author_facet | Ramla Omar Michelle AW Lee Laura Gonzalez-Trueba Cameron R. Thomson Uwe Hansen Spyridonas Lianos Snoopy Hazarika Omar HMEH El Abdallah Malak A. Ammar Jennifer Cassels Alison M. Michie Neil J. Bulleid Fransiska Malfait Tom Van Agtmael |
| author_sort | Ramla Omar |
| collection | DOAJ |
| description | Abstract Vascular Ehlers Danlos Syndrome (vEDS) is a connective tissue disorder caused by COL3A1 mutations for which there are no treatments due to a limited understanding of underlying mechanisms. We aimed to identify the molecular insults of mutations, focusing on collagen folding, to establish if targeting protein folding represents a potential therapeutic approach. Analysis of two novel COL3A1 glycine mutations, G189S and G906R, in primary patient fibroblast cultures revealed secretion of misfolded collagen III and intracellular collagen retention leading to lower extracellular collagen levels. This was associated with matrix defects, endoplasmic reticulum (ER) stress, reduced cell proliferation and apoptosis. The ER stress was mediated by activation of IRE1 and PERK signalling arms with evidence of allelic heterogeneity. To establish if promoting ER protein folding capacity or protein degradation represents novel therapeutic avenues, we investigated the efficacy of FDA-approved small molecules. The chemical chaperone 4-phenylbutyric acid (PBA) rescued the ER stress and thermostability of secreted collagen leading to reduced apoptosis and matrix defects, and its efficacy was influenced by duration, dosage and allelic heterogeneity. Targeting protein degradation with carbamazepine (CBZ), or PBA-CBZ in combination did not increase treatment efficacy. These data establish that ER stress is a molecular mechanism in vEDS that can be influenced by the position of COL3A1 mutation. It combines with matrix defects due to reduced collagen III levels and/or mutant protein secretion to vEDS pathogenesis. Targeting protein folding using FDA-approved chemical chaperones represents a putative mechanism-based therapeutic approach for vEDS that can rescue intra- and extracellular defects. |
| format | Article |
| id | doaj-art-08d2aa2d355549ffbd941670e8803153 |
| institution | DOAJ |
| issn | 2058-7716 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death Discovery |
| spelling | doaj-art-08d2aa2d355549ffbd941670e88031532025-08-20T03:08:24ZengNature Publishing GroupCell Death Discovery2058-77162025-04-0111111110.1038/s41420-025-02476-yThe chemical chaperone 4-phenylbutyric acid rescues molecular cell defects of COL3A1 mutations that cause vascular Ehlers Danlos SyndromeRamla Omar0Michelle AW Lee1Laura Gonzalez-Trueba2Cameron R. Thomson3Uwe Hansen4Spyridonas Lianos5Snoopy Hazarika6Omar HMEH El Abdallah7Malak A. Ammar8Jennifer Cassels9Alison M. Michie10Neil J. Bulleid11Fransiska Malfait12Tom Van Agtmael13School of Cardiovascular and Metabolic Health, College of Medical, Veterinary & Life Sciences, University of GlasgowSchool of Cardiovascular and Metabolic Health, College of Medical, Veterinary & Life Sciences, University of GlasgowSchool of Cardiovascular and Metabolic Health, College of Medical, Veterinary & Life Sciences, University of GlasgowSchool of Cardiovascular and Metabolic Health, College of Medical, Veterinary & Life Sciences, University of GlasgowInstitute of Musculoskeletal Medicine, University of Muenster, University Hospital MuensterSchool of Cardiovascular and Metabolic Health, College of Medical, Veterinary & Life Sciences, University of GlasgowSchool of Cardiovascular and Metabolic Health, College of Medical, Veterinary & Life Sciences, University of GlasgowSchool of Cardiovascular and Metabolic Health, College of Medical, Veterinary & Life Sciences, University of GlasgowSchool of Cardiovascular and Metabolic Health, College of Medical, Veterinary & Life Sciences, University of GlasgowPaul O’Gorman Leukaemia Research Centre, School of Cancer Studies, College of Medical, Veterinary & Life Sciences, University of GlasgowPaul O’Gorman Leukaemia Research Centre, School of Cancer Studies, College of Medical, Veterinary & Life Sciences, University of GlasgowSchool of Molecular Biosciences, College of Medical, Veterinary & Life Sciences, University of GlasgowCenter for Medical Genetics, Ghent University Hospital and Department for Biomolecular Medicine, Ghent UniversitySchool of Cardiovascular and Metabolic Health, College of Medical, Veterinary & Life Sciences, University of GlasgowAbstract Vascular Ehlers Danlos Syndrome (vEDS) is a connective tissue disorder caused by COL3A1 mutations for which there are no treatments due to a limited understanding of underlying mechanisms. We aimed to identify the molecular insults of mutations, focusing on collagen folding, to establish if targeting protein folding represents a potential therapeutic approach. Analysis of two novel COL3A1 glycine mutations, G189S and G906R, in primary patient fibroblast cultures revealed secretion of misfolded collagen III and intracellular collagen retention leading to lower extracellular collagen levels. This was associated with matrix defects, endoplasmic reticulum (ER) stress, reduced cell proliferation and apoptosis. The ER stress was mediated by activation of IRE1 and PERK signalling arms with evidence of allelic heterogeneity. To establish if promoting ER protein folding capacity or protein degradation represents novel therapeutic avenues, we investigated the efficacy of FDA-approved small molecules. The chemical chaperone 4-phenylbutyric acid (PBA) rescued the ER stress and thermostability of secreted collagen leading to reduced apoptosis and matrix defects, and its efficacy was influenced by duration, dosage and allelic heterogeneity. Targeting protein degradation with carbamazepine (CBZ), or PBA-CBZ in combination did not increase treatment efficacy. These data establish that ER stress is a molecular mechanism in vEDS that can be influenced by the position of COL3A1 mutation. It combines with matrix defects due to reduced collagen III levels and/or mutant protein secretion to vEDS pathogenesis. Targeting protein folding using FDA-approved chemical chaperones represents a putative mechanism-based therapeutic approach for vEDS that can rescue intra- and extracellular defects.https://doi.org/10.1038/s41420-025-02476-y |
| spellingShingle | Ramla Omar Michelle AW Lee Laura Gonzalez-Trueba Cameron R. Thomson Uwe Hansen Spyridonas Lianos Snoopy Hazarika Omar HMEH El Abdallah Malak A. Ammar Jennifer Cassels Alison M. Michie Neil J. Bulleid Fransiska Malfait Tom Van Agtmael The chemical chaperone 4-phenylbutyric acid rescues molecular cell defects of COL3A1 mutations that cause vascular Ehlers Danlos Syndrome Cell Death Discovery |
| title | The chemical chaperone 4-phenylbutyric acid rescues molecular cell defects of COL3A1 mutations that cause vascular Ehlers Danlos Syndrome |
| title_full | The chemical chaperone 4-phenylbutyric acid rescues molecular cell defects of COL3A1 mutations that cause vascular Ehlers Danlos Syndrome |
| title_fullStr | The chemical chaperone 4-phenylbutyric acid rescues molecular cell defects of COL3A1 mutations that cause vascular Ehlers Danlos Syndrome |
| title_full_unstemmed | The chemical chaperone 4-phenylbutyric acid rescues molecular cell defects of COL3A1 mutations that cause vascular Ehlers Danlos Syndrome |
| title_short | The chemical chaperone 4-phenylbutyric acid rescues molecular cell defects of COL3A1 mutations that cause vascular Ehlers Danlos Syndrome |
| title_sort | chemical chaperone 4 phenylbutyric acid rescues molecular cell defects of col3a1 mutations that cause vascular ehlers danlos syndrome |
| url | https://doi.org/10.1038/s41420-025-02476-y |
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