Oct-1 recruitment to the nuclear envelope in adult-onset autosomal dominant leukodystrophy.

Adult-onset autosomal dominant leukodystrophy (ADLD) is a slowly progressive neurological disorder
characterized 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 analyzed
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 localization 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
disorganization 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 localization contributes to the disease phenotype.