دورية أكاديمية

The small compound Icerguastat reduces muscle defects in oculopharyngeal muscular dystrophy through the PERK pathway of the unfolded protein response

التفاصيل البيبلوغرافية
العنوان: The small compound Icerguastat reduces muscle defects in oculopharyngeal muscular dystrophy through the PERK pathway of the unfolded protein response
المؤلفون: Naït-Saïdi, Rima, Chartier, Aymeric, Abgueguen, Emmanuelle, Guédat, Philippe, Simonelig, Martine
المساهمون: Institut de génétique humaine (IGH), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), ANR-17-CE12-0011,riboOPMD,ARN ribosomiques et petits ARN non-codants dans la dystrophie musculaire oculopharyngée(2017)
المصدر: EISSN: 2046-2441 ; Open Biology ; https://hal.science/hal-04121825Test ; Open Biology, 2023, 13 (4), pp.230008. ⟨10.1098/rsob.230008⟩
بيانات النشر: HAL CCSD
Royal Society
سنة النشر: 2023
المجموعة: Université de Montpellier: HAL
مصطلحات موضوعية: Drosophila model, GADD34, Icerguastat/IFB-088, OPMD, PEK/PERK, Unfolded protein response, MESH: Animals, MESH: Muscular Dystrophy, Oculopharyngeal, MESH: Muscle, Skeletal, MESH: Unfolded Protein Response, MESH: Cell Nucleus, MESH: Endoplasmic Reticulum Stress, MESH: Drosophila, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology
الوصف: International audience ; Oculopharyngeal muscular dystrophy (OPMD) is an autosomal dominant disease characterized by the progressive degeneration of specific muscles. OPMD is due to a mutation in the gene encoding poly(A) binding protein nuclear 1 (PABPN1) leading to a stretch of 11 to 18 alanines at N-terminus of the protein, instead of 10 alanines in the normal protein. This alanine tract extension induces the misfolding and aggregation of PABPN1 in muscle nuclei. Here, using Drosophila OPMD models, we show that the unfolded protein response (UPR) is activated in OPMD upon endoplasmic reticulum stress. Mutations in components of the PERK branch of the UPR reduce muscle degeneration and PABPN1 aggregation characteristic of the disease. We show that oral treatment of OPMD flies with Icerguastat (previously IFB-088), a Guanabenz acetate derivative that shows lower side effects, also decreases muscle degeneration and PABPN1 aggregation. Furthermore, the positive effect of Icerguastat depends on GADD34, a key component of the phosphatase complex in the PERK branch of the UPR. This study reveals a major contribution of the ER stress in OPMD pathogenesis and provides a proof-of-concept for Icerguastat interest in future pharmacological treatments of OPMD.
نوع الوثيقة: article in journal/newspaper
اللغة: English
العلاقة: info:eu-repo/semantics/altIdentifier/pmid/37042114; hal-04121825; https://hal.science/hal-04121825Test; https://hal.science/hal-04121825/documentTest; https://hal.science/hal-04121825/file/Nait-Saidi%20et%20al.2023.pdfTest; PUBMED: 37042114; PUBMEDCENTRAL: PMC10090878; WOS: 000969186000002
DOI: 10.1098/rsob.230008
الإتاحة: https://doi.org/10.1098/rsob.230008Test
https://hal.science/hal-04121825Test
https://hal.science/hal-04121825/documentTest
https://hal.science/hal-04121825/file/Nait-Saidi%20et%20al.2023.pdfTest
حقوق: http://creativecommons.org/licenses/byTest/ ; info:eu-repo/semantics/OpenAccess
رقم الانضمام: edsbas.B41D8E08
قاعدة البيانات: BASE