Evaluation of the endoplasmic reticulum-stress response in eIF2B-mutated lymphocytes and lymphoblasts from CACH/VWM patients
| Autor: | Liraz Kantor, Anne Fogli, Orna Elroy-Stein, Raphael Schiffmann, Odile Boespflug-Tanguy, Laetitia Horzinski, Aurélia Huyghe |
|---|---|
| Přispěvatelé: | BMC, Ed., Génétique, Reproduction et Développement (GReD), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre National de la Recherche Scientifique (CNRS), Department of Cell Research and Immunology, Tel Aviv University (TAU), Institute of Metabolic Disease, Baylor College of Medecine, Service de Génétique Médicale [CHU Clermont-Ferrand], CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand, Centre de Référence Leucodystrophies, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Clermont-Ferrand-Hôpital Saint-Vincent de Paul, Service de Biochimie Médicale et Biologie Moléculaire, CHU Clermont-Ferrand, The authors thank the European Leukodystrophy Association (ELA), grant 2005-2007 (project #11)., Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Institut National de la Santé et de la Recherche Médicale (INSERM), Tel Aviv University [Tel Aviv] |
| Rok vydání: | 2010 |
| Předmět: |
Male
MESH: Thapsigargin Endoplasmic Reticulum lcsh:RC346-429 chemistry.chemical_compound 0302 clinical medicine Leukoencephalopathies MESH: Reverse Transcriptase Polymerase Chain Reaction MESH: Child Protein biosynthesis Medicine Lymphocytes Enzyme Inhibitors MESH: Stress Physiological Child Endoplasmic Reticulum Chaperone BiP 0303 health sciences biology Reverse Transcriptase Polymerase Chain Reaction General Medicine MESH: Infant Cell biology Eukaryotic Initiation Factor-2B MESH: Enzyme Inhibitors MESH: Protein Biosynthesis Child Preschool eIF2B Thapsigargin [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] Female Research Article MESH: Mutation Adolescent Blotting Western Clinical Neurology Activating Transcription Factor 4 MESH: Leukoencephalopathies Cell Line 03 medical and health sciences Eukaryotic translation MESH: Endoplasmic Reticulum Stress Physiological MESH: Activating Transcription Factor 4 MESH: Blotting Western Humans [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] lcsh:Neurology. Diseases of the nervous system 030304 developmental biology MESH: Adolescent MESH: Humans business.industry Endoplasmic reticulum MESH: Child Preschool ATF4 Infant MESH: Eukaryotic Initiation Factor-2B MESH: Male MESH: Cell Line chemistry Protein Biosynthesis Mutation Unfolded protein response biology.protein MESH: Lymphocytes Neurology (clinical) business MESH: Female 030217 neurology & neurosurgery |
| Zdroj: | BMC Neurology BMC Neurology, 2010, 10 (1), pp.94. ⟨10.1186/1471-2377-10-94⟩ BMC Neurology, BioMed Central, 2010, 10 (1), pp.94. ⟨10.1186/1471-2377-10-94⟩ BMC Neurology, Vol 10, Iss 1, p 94 (2010) |
| ISSN: | 1471-2377 |
| DOI: | 10.1186/1471-2377-10-94 |
| Popis: | Background Eukaryotic translation initiation factor 2B (eIF2B), a guanine nucleotide exchange factor (GEF) and a key regulator of translation initiation under normal and stress conditions, causes an autosomal recessive leukodystrophy of a wide clinical spectrum. EBV-immortalised lymphocytes (EIL) from eIF2B-mutated patients exhibit a decrease in eIF2B GEF activity. eIF2B-mutated primary fibroblasts have a hyper-induction of activating transcription factor 4 (ATF4) which is involved in the protective unfolded protein response (UPR), also known as the ER-stress response. We tested the hypothesis that EIL from eIF2B-mutated patients also exhibit a heightened ER-stress response. Methods We used thapsigargin as an ER-stress agent and looked at polysomal profiles, rate of protein synthesis, translational activation of ATF4, and transcriptional induction of stress-specific mRNAs (ATF4, CHOP, ASNS, GRP78) in normal and eIF2B-mutated EIL. We also compared the level of stress-specific mRNAs between EIL and primary lymphocytes (PL). Results Despite the low eIF2B GEF activity in the 12 eIF2B-mutated EIL cell lines tested (range 40-70% of normal), these cell lines did not differ from normal EIL in their ATF4-mediated ER-stress response. The absence of hyper-induction of ATF4-mediated ER-stress response in eIF2B-mutated EIL in contrast to primary fibroblasts is not related to their transformation by EBV. Indeed, PL exhibited a higher induction of the stress-specific mRNAs in comparison to EIL, but no hyper-induction of the UPR was noticed in the eIF2B-mutated cell lines in comparison to controls. Conclusions Taken together with work of others, our results demonstrate the absence of a major difference in ER-stress response between controls and eIF2B-mutated cells. Therefore, components of the ER-stress response cannot be used as discriminantory markers in eIF2B-related disorders. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|