دورية أكاديمية
أعرض في EDS

Increased intracellular proteolysis reduces disease severity in an ER stress-associated dwarfism.

التفاصيل البيبلوغرافية
العنوان: Increased intracellular proteolysis reduces disease severity in an ER stress-associated dwarfism.
المؤلفون: Mullan LA; Wellcome Trust Centre for Cell-Matrix Research.; Faculty of Biology, Medicine and Health, and Manchester Academic Health Science Centre, Manchester, United Kingdom., Mularczyk EJ; Wellcome Trust Centre for Cell-Matrix Research.; Faculty of Biology, Medicine and Health, and Manchester Academic Health Science Centre, Manchester, United Kingdom., Kung LH; Wellcome Trust Centre for Cell-Matrix Research.; Faculty of Biology, Medicine and Health, and Manchester Academic Health Science Centre, Manchester, United Kingdom.; Murdoch Children's Research Institute, Parkville, Victoria, Australia., Forouhan M; Wellcome Trust Centre for Cell-Matrix Research.; Faculty of Biology, Medicine and Health, and Manchester Academic Health Science Centre, Manchester, United Kingdom., Wragg JM; Wellcome Trust Centre for Cell-Matrix Research.; Faculty of Biology, Medicine and Health, and Manchester Academic Health Science Centre, Manchester, United Kingdom., Goodacre R; School of Chemistry and Manchester Institute of Biotechnology, Faculty of Science and Engineering, University of Manchester, Manchester, United Kingdom., Bateman JF; Murdoch Children's Research Institute, Parkville, Victoria, Australia., Swanton E; Faculty of Biology, Medicine and Health, and Manchester Academic Health Science Centre, Manchester, United Kingdom., Briggs MD; Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom., Boot-Handford RP; Wellcome Trust Centre for Cell-Matrix Research.; Faculty of Biology, Medicine and Health, and Manchester Academic Health Science Centre, Manchester, United Kingdom.
المصدر: The Journal of clinical investigation [J Clin Invest] 2017 Oct 02; Vol. 127 (10), pp. 3861-3865. Date of Electronic Publication: 2017 Sep 18.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: American Society for Clinical Investigation Country of Publication: United States NLM ID: 7802877 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1558-8238 (Electronic) Linking ISSN: 00219738 NLM ISO Abbreviation: J Clin Invest Subsets: MEDLINE
أسماء مطبوعة: Publication: 1999- : Ann Arbor, MI : American Society for Clinical Investigation
Original Publication: New Haven [etc.] American Society for Clinical Investigation.
مواضيع طبية MeSH: Endoplasmic Reticulum Stress* , Mutation* , Proteolysis*, Carbamazepine/*pharmacology , Chondrocytes/*metabolism , Collagen Type X/*biosynthesis , Dwarfism/*metabolism, Activating Transcription Factor 4/genetics ; Activating Transcription Factor 4/metabolism ; Animals ; Chondrocytes/pathology ; Collagen Type X/genetics ; Dwarfism/genetics ; Dwarfism/pathology ; Endoplasmic Reticulum Chaperone BiP ; Heat-Shock Proteins/genetics ; Heat-Shock Proteins/metabolism ; Humans ; Mice
مستخلص: The short-limbed dwarfism metaphyseal chondrodysplasia type Schmid (MCDS) is linked to mutations in type X collagen, which increase ER stress by inducing misfolding of the mutant protein and subsequently disrupting hypertrophic chondrocyte differentiation. Here, we show that carbamazepine (CBZ), an autophagy-stimulating drug that is clinically approved for the treatment of seizures and bipolar disease, reduced the ER stress induced by 4 different MCDS-causing mutant forms of collagen X in human cell culture. Depending on the nature of the mutation, CBZ application stimulated proteolysis of misfolded collagen X by either autophagy or proteasomal degradation, thereby reducing intracellular accumulation of mutant collagen. In MCDS mice expressing the Col10a1.pN617K mutation, CBZ reduced the MCDS-associated expansion of the growth plate hypertrophic zone, attenuated enhanced expression of ER stress markers such as Bip and Atf4, increased bone growth, and reduced skeletal dysplasia. CBZ produced these beneficial effects by reducing the MCDS-associated abnormalities in hypertrophic chondrocyte differentiation. Stimulation of intracellular proteolysis using CBZ treatment may therefore be a clinically viable way of treating the ER stress-associated dwarfism MCDS.
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معلومات مُعتمدة: United Kingdom Wellcome Trust
المشرفين على المادة: 0 (ATF4 protein, human)
0 (Atf4 protein, mouse)
0 (Col10a1 protein, mouse)
0 (Collagen Type X)
0 (Endoplasmic Reticulum Chaperone BiP)
0 (Heat-Shock Proteins)
145891-90-3 (Activating Transcription Factor 4)
33CM23913M (Carbamazepine)
تواريخ الأحداث: Date Created: 20170919 Date Completed: 20171019 Latest Revision: 20211204
رمز التحديث: 20231215
مُعرف محوري في PubMed: PMC5617653
DOI: 10.1172/JCI93094
PMID: 28920921
قاعدة البيانات: MEDLINE
الوصف
تدمد:1558-8238
DOI:10.1172/JCI93094