Gene Expression Profiling in Tibial Muscular Dystrophy Reveals Unfolded Protein Response and Altered Autophagy
| Autor: | Per Harald Jonson, Mark Screen, Sanna Huovinen, Bjarne Udd, Peter Hackman, Olayinka Raheem, Jeanette Holmlund-Hampf |
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| Přispěvatelé: | Department of Medical and Clinical Genetics, Haartman Institute (-2014), Lääketieteen yksikkö - School of Medicine, University of Tampere |
| Jazyk: | angličtina |
| Rok vydání: | 2014 |
| Předmět: |
Male
Pathology Anatomy and Physiology Microarrays VALOSIN-CONTAINING PROTEIN Biopsy lcsh:Medicine Muscular Dystrophies DISEASE 0302 clinical medicine ENDOPLASMIC-RETICULUM STRESS INCLUSION-BODY MYOSITIS Molecular Cell Biology Myocyte Cluster Analysis C-TERMINAL TITIN lcsh:Science Endoplasmic Reticulum Chaperone BiP Musculoskeletal System Cellular Stress Responses Aged 80 and over 0303 health sciences Multidisciplinary biology Muscles Endoplasmic Reticulum-Associated Degradation Genomics Neuromuscular Diseases Middle Aged ER STRESS MUSCLE RIMMED VACUOLES Cell biology Neurology Autosomal Dominant Medicine Titin Female medicine.symptom Cellular Types Neurotieteet - Neurosciences Signal Transduction Research Article Adult medicine.medical_specialty XBP1 Histology Valosin-containing protein education Endoplasmic-reticulum-associated protein degradation Muscle Fibers 03 medical and health sciences DISTAL MYOPATHY medicine Autophagy Humans Myopathy Biology 030304 developmental biology Aged Clinical Genetics Muscle Cells MUTATIONS Endoplasmic reticulum Gene Expression Profiling lcsh:R Computational Biology Distal Myopathies Case-Control Studies biology.protein Unfolded protein response Unfolded Protein Response lcsh:Q 3111 Biomedicine Transcriptome Genome Expression Analysis 030217 neurology & neurosurgery |
| Zdroj: | PLoS ONE PLoS ONE, Vol 9, Iss 3, p e90819 (2014) |
| Popis: | Tibial muscular dystrophy (TMD) is a late onset, autosomal dominant distal myopathy that results from mutations in the two last domains of titin. The cascade of molecular events leading from the causative Titin mutations to the preterm death of muscle cells in TMD is largely unknown. In this study we examined the mRNA and protein changes associated with the myopathology of TMD. To identify these components we performed gene expression profiling using muscle biopsies from TMD patients and healthy controls. The profiling results were confirmed through quantitative real-time PCR and protein level analysis. One of the pathways identified was activation of endoplasmic reticulum (ER) stress response. ER stress activates the unfolded protein response (UPR) pathway. UPR activation was supported by elevation of the marker genes HSPA5, ERN1 and the UPR specific XBP1 splice form. However, UPR activation appears to be insufficient to correct the protein abnormalities causing its activation because degenerative TMD muscle fibres show an increase in ubiquitinated protein inclusions. Abnormalities of VCP-associated degradation pathways are also suggested by the presence of proteolytic VCP fragments in western blotting, and VCP's accumulation within rimmed vacuoles in TMD muscle fibres together with p62 and LC3B positive autophagosomes. Thus, pathways controlling turnover and degradation, including autophagy, are distorted and lead to degeneration and loss of muscle fibres. Public Library of Science open access |
| Databáze: | OpenAIRE |
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