Dysregulation of GSK3β-Target Proteins in Skin Fibroblasts of Myotonic Dystrophy Type 1 (DM1) Patients
| Autor: | Geneviève Gourdon, Andreas Hentschel, Hanns Lochmüller, Denisa Hathazi, Valentina Grande, Nikoletta Nikolenko, Ulrike Schara-Schmidt, Theo Marteau, Andreas Roos, Emily O'Connor |
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| Přispěvatelé: | Universitat Duisberg-Essen, Leibniz-Institut für Analytische Wissenschaften - ISAS - e.V., University of Cambridge School of Clinical Medicine, Université d'Ottawa [Ontario] (uOttawa), Essen University Hospital, Centre de recherche en Myologie – U974 SU-INSERM, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), University College London Hospitals (UCLH), University Hospital Freiburg, Barcelona Institute of Science and Technology (BIST), University Children's Hospital of Essen [Essen, Germany], HAL UPMC, Gestionnaire, Centre de Recherche en Myologie |
| Rok vydání: | 2021 |
| Předmět: |
Male
Proteomics 0301 basic medicine [SDV]Life Sciences [q-bio] Muscle Fibers Skeletal Medizin MAP2K2 Muscle Development CTPS1 CAPN1 0302 clinical medicine Myotonic Dystrophy CTNNB1 Skin Myogenesis Kinase Middle Aged 3. Good health Cell biology [SDV] Life Sciences [q-bio] medicine.anatomical_structure Neurology Female Adult musculoskeletal diseases congenital hereditary and neonatal diseases and abnormalities Myosin light-chain kinase Protein Serine-Threonine Kinases Biology Myotonic dystrophy Myotonin-Protein Kinase 03 medical and health sciences medicine Humans Muscle Strength RNA Messenger Protein kinase A GSK3B Glycogen Synthase Kinase 3 beta Gene Expression Profiling Skeletal muscle Fibroblasts medicine.disease HDAC2 030104 developmental biology fibroblast proteomics GSK3 Neurology (clinical) Trinucleotide Repeat Expansion Biomarkers 030217 neurology & neurosurgery |
| Zdroj: | Journal of Neuromuscular Diseases Journal of Neuromuscular Diseases, IOS Press, 2021, 8, pp.603-619. ⟨10.3233/jnd-200558⟩ Journal of Neuromuscular Diseases, 2021, 8, pp.603-619. ⟨10.3233/jnd-200558⟩ |
| ISSN: | 2214-3602 2214-3599 2600-3600 |
| DOI: | 10.3233/jnd-200558 |
| Popis: | International audience; Myotonic dystrophy type 1 (DM1) is the most common monogenetic muscular disorder of adulthood. This multisystemic disease is caused by CTG repeat expansion in the 3-untranslated region of the DM1 protein kinase gene called DMPK. DMPK encodes a myosin kinase expressed in skeletal muscle cells and other cellular populations such as smooth muscle cells, neurons and fibroblasts. The resultant expanded (CUG)n RNA transcripts sequester RNA binding factors leading to ubiquitous and persistent splicing deregulation. The accumulation of mutant CUG repeats is linked to increased activity of glycogen synthase kinase 3 beta (GSK3), a highly conserved and ubiquitous serine/threonine kinase with functions in pathways regulating inflammation, metabolism, oncogenesis, neurogenesis and myogenesis. As GSK3-inhibition ameliorates defects in myogenesis, muscle strength and myotonia in a DM1 mouse model, this kinase represents a key player of DM1 pathobiochemistry and constitutes a promising therapeutic target. To better characterise DM1 patients, and monitor treatment responses, we aimed to define a set of robust disease and severity markers linked to GSK3by unbiased proteomic profiling utilizing fibroblasts derived from DM1 patients with low (80-150) and high (2600-3600) CTG-repeats. Apart from GSK3 increase, we identified dysregulation of nine proteins (CAPN1, CTNNB1, CTPS1, DNMT1, HDAC2, HNRNPH3, MAP2K2, NR3C1, VDAC2) modulated by GSK3. In silico-based expression studies confirmed expression in neuronal and skeletal muscle cells and revealed a relatively elevated abundance in fibroblasts. The potential impact of each marker in the myopathology of DM1 is discussed based on respective function to inform potential uses as severity markers or for monitoring GSK3 inhibitor treatment responses. |
| Databáze: | OpenAIRE |
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