title: Oct-1 recruitment to the nuclear envelope in adult-onset autosomal dominant leukodystrophy.
abstract: 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.
authors.affiliation: Rizzoli Orthopaedic Institute, Bologna, Italy.
authors.forename: Marta
authors.initials: M
authors.lastname: Columbaro
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Mattioli
authors.forename: Nadir M
authors.initials: NM
authors.lastname: Maraldi
authors.forename: Michela
authors.initials: M
authors.lastname: Ortolani
authors.forename: Laura
authors.initials: L
authors.lastname: Gasparini
authors.forename: Maria Rosaria
authors.initials: MR
authors.lastname: D'Apice
authors.forename: Diana
authors.initials: D
authors.lastname: Postorivo
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Nardone
authors.forename: Sofia
authors.initials: S
authors.lastname: Avnet
authors.forename: Pietro
authors.initials: P
authors.lastname: Cortelli
authors.forename: Rocco
authors.initials: R
authors.lastname: Liguori
authors.forename: Giovanna
authors.initials: G
authors.lastname: Lattanzi
mesh_terms: D015153:Blotting, Western; D002467:Cell Nucleus / Q000378:metabolism / Q000648:ultrastructure; D002478:Cells, Cultured; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D020440:Gene Duplication; D006801:Humans; D034921:Lamin Type B / Q000235:genetics / Q000378:metabolism*; D008297:Male; D046529:Microscopy, Electron, Transmission; D008856:Microscopy, Fluorescence; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000378:metabolism / Q000648:ultrastructure; D009685:Nuclear Envelope / Q000378:metabolism* / Q000648:ultrastructure; D050811:Octamer Transcription Factor-1 / Q000378:metabolism*; D020371:Pelizaeus-Merzbacher Disease / Q000235:genetics / Q000378:metabolism*
chemical_list: D034921:Lamin Type B; D050811:Octamer Transcription Factor-1