Oct-1 recruitment to the nuclear envelope in adult-onset autosomal dominant leukodystrophy
| Autor: | Michela Ortolani, Giovanna Lattanzi, Elisabetta Mattioli, Maria Rosaria D'Apice, Marta Columbaro, Sofia Avnet, Diana Postorivo, Pietro Cortelli, Nadir M. Maraldi, Laura Gasparini, Anna Maria Nardone, Rocco Liguori |
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| Přispěvatelé: | M. Columbaro, E. Mattioli, N. M. Maraldi, M. Ortolani, L. Gasparini, M. R. D'Apice, D. Postorivo, A. M. Nardone, S. Avnet, P. Cortelli, R. Liguori, G. Lattanzi |
| Jazyk: | angličtina |
| Rok vydání: | 2013 |
| Předmět: |
Male
genetics/metabolism Male Microscopy Pelizaeus-Merzbacher Disease genetics/metabolism metabolism/ultrastructure Octamer Transcription Factor-1 Sarcomere Oct-1 IIB-myosin heavy chain Western Cell Nucleu metabolism Gene Duplication Humans Lamin Type B Gene Duplication Gene duplication Lamin B1 Cells Cultured Lamin Type B Blotting Fluorescence Middle Aged Muscle Skeletal Middle Aged Phenotype medicine.anatomical_structure Molecular Medicine Female Nuclear Envelope Blotting Western metabolism/ultrastructure Cell Protein degradation Biology Electron Autosomal dominant leukodystrophy (ADLD) Microscopy Electron Transmission medicine Cultured Female Fibroblast Humans Muscle Skeletal Transcription factor Molecular Biology Cell Nucleus metabolism Pelizaeus-Merzbacher Disease Leukodystrophy Skeletal muscle Fibroblasts medicine.disease Molecular biology Microscopy Fluorescence Transmission Microscopy metabolism/ultrastructure Nuclear Envelope Lamin Octamer Transcription Factor-1 |
| Popis: | Adult-onset autosomal dominant leukodystrophy (ADLD) is a slowly progressive neurological disorder characterised by pyramidal, cerebellar, and autonomic disturbances. Duplication of the LMNB1 gene is the genetic cause of ADLD, yet the pathogenetic mechanism is not defined. In this study, we analysed cells and muscle tissue from three patients affected by ADLD, carrying an extra copy of the LMNB1 gene. Lamin B1 levels were dramatically increased in ADLD nuclei, both in skin fibroblasts and skeletal muscle fibres. Since lamin B1 is known to bind Oct-1, a transcription factor involved in the oxidative stress pathway, we investigated Oct-1 fate in ADLD. Oct-1 recruitment to the nuclear periphery was increased in ADLD cells, while nucleoplasmic localisation of the transcription factor under oxidative stress conditions was reduced. Importantly, lamin B1 degradation occurring in some, but not all ADLD cell lines, slowed down lamin B1 and Oct-1 accumulation. In skeletal muscle, focal disorganisation of sarcomeres was observed, while IIB-myosin heavy chain, an Oct-1 target gene, was under-expressed and rod-containing fibres were formed. These data show that a high degree of regulation of lamin B1 expression is implicated in the different clinical phenotypes observed in ADLD and show that altered Oct-1 nuclear localisation contributes to the disease phenotype. |
| Databáze: | OpenAIRE |
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