Disease-related amyloidogenic variants of human lysozyme trigger the unfolded protein response and disturb eye development in Drosophila melanogaster
| العنوان: | Disease-related amyloidogenic variants of human lysozyme trigger the unfolded protein response and disturb eye development in Drosophila melanogaster |
|---|---|
| المؤلفون: | Jocy Williams, Leila M. Luheshi, Christopher M. Dobson, Ann-Christin Brorsson, Linda Menzer, Damian C. Crowther, Janet R. Kumita, Mireille Dumoulin, Linda Helmfors, David A. Lomas |
| المصدر: | The FASEB Journal |
| بيانات النشر: | Federation of American Societies for Experimental Biology, 2012. |
| سنة النشر: | 2012 |
| مصطلحات موضوعية: | Male, Green Fluorescent Proteins, xbp1-EGFP, Biochemistry, Research Communications, Animals, Genetically Modified, 03 medical and health sciences, chemistry.chemical_compound, Amyloid disease, 0302 clinical medicine, Hemolymph, Gene expression, Naturvetenskap, Genetics, Animals, Drosophila Proteins, Humans, Secretion, Eye Abnormalities, Molecular Biology, 030304 developmental biology, 0303 health sciences, biology, fungi, Metamorphosis, Biological, quality control system, Amyloidosis, biology.organism_classification, Endoplasmic Reticulum Stress, Molecular biology, DNA-Binding Proteins, Disease Models, Animal, Drosophila melanogaster, chemistry, Solubility, Eye development, Unfolded protein response, Microscopy, Electron, Scanning, Unfolded Protein Response, Female, Muramidase, Photoreceptor Cells, Invertebrate, Lysozyme, Natural Sciences, ER stress, 030217 neurology & neurosurgery, Drosophila Protein, Biotechnology |
| الوصف: | We have created a Drosophila model of lysozyme amyloidosis to investigate the in vivo behavior of disease-associated variants. To achieve this objective, wild-type (WT) protein and the amyloidogenic variants F57I and D67H were expressed in Drosophila melanogaster using the UAS-gal4 system and both the ubiquitous and retinal expression drivers Act5C-gal4 and gmr-gal4. The nontransgenic w(1118) Drosophila line was used as a control throughout. We utilized ELISA experiments to probe lysozyme protein levels, scanning electron microscopy for eye phenotype classification, and immunohistochemistry to detect the unfolded protein response (UPR) activation. We observed that expressing the destabilized F57I and D67H lysozymes triggers UPR activation, resulting in degradation of these variants, whereas the WT lysozyme is secreted into the fly hemolymph. Indeed, the level of WT was up to 17 times more abundant than the variant proteins. In addition, the F57I variant gave rise to a significant disruption of the eye development, and this correlated to pronounced UPR activation. These results support the concept that the onset of familial amyloid disease is linked to an inability of the UPR to degrade completely the amyloidogenic lysozymes prior to secretion, resulting in secretion of these destabilized variants, thereby leading to deposition and associated organ damage.-Kumita, J. R., Helmfors, L., Williams, J., Luheshi, L. M., Menzer, L., Dumoulin, M., Lomas, D. A., Crowther, D. C., Dobson, C. M., Brorsson, A.-C. Disease-related amyloidogenic variants of human lysozyme trigger the unfolded protein response and disturb eye development in Drosophila melanogaster. funding agencies|Swedish Research Council||Biotechnology and Biological Sciences Research Council| BB/E019927/1 BBH0038431 |Wellcome Trust||Leverhulme Trust||European Commission| LSHM-CT-2006-037525/EURAMY |Medical Research Council| G0700990 |VINNOVA |
| وصف الملف: | application/pdf |
| اللغة: | English |
| تدمد: | 1530-6860 0892-6638 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::d00542b5068451f6123191d1b1e2b33c http://europepmc.org/articles/PMC3250245 |
| Rights: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....d00542b5068451f6123191d1b1e2b33c |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15306860 08926638 |
|---|