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.

Centenarian lamins: rapamycin targets in longevity

“…The latter data support the link between accumulation of farnesylated prelamin A and recruitment of SUN1 to the nuclear envelope, as previously shown in HGPS cells (Haque et al, 2010) and normal human muscle (Mattioli et al, 2011). Moreover, given that recent data have clearly shown downregulation of lamin B1 in oncogene-induced cellular senescence and upregulation of lamin B1 in cells subjected to oxidative stress (Barascu et al, 2012;Columbaro et al, 2013;Dreesen et al, 2013;Freund et al, 2012;Shimi et al, 2011), the evidence that lamin B1 is not significantly affected in CE fibroblasts ( Fig. 2A,C) supports the notion that these cells maintain a 'young-like phenotype'.…”

Diverse lamin-dependent mechanisms interact to control chromatin dynamics

“…Heterochromatin disorganization and altered import of the transcription factor Oct-1 in nuclei have been reported in ADLD 61 . Of note, Oct-1 sequestering in ADLD muscle nuclei impairs transcription of Myosyn heavy chain 2B, one of the Oct-1 target genes, playing a major role in muscle function 61 . The latter finding involves regulation of muscle genes in ADLD pathophysiology, consistent with clinical and morphological observations 61 .…”

“…This has been shown for SREBP1, Sp1, and Oct-1, which interact with prelamin A 56 - 58 and for pRb, Mok2, and cFos, which bind mature lamin A or lamin C 59 , 60 . Also lamin B1 is able to recruit the transcription factor Oct-1 to the nuclear envelope 61 , 62 . Most of these interactions elicit an inhibitory effect on gene activity, indicating the nuclear envelope as a gate or a resting place for transcriptional regulators 56 , 63 , 64 .…”

“…It is caused by LMNB1 duplication and features high levels of lamin B1 accumulation in nuclei at the onset of disease, which occurs around the fourth decade 61 . Heterochromatin disorganization and altered import of the transcription factor Oct-1 in nuclei have been reported in ADLD 61 .…”

“…It is caused by LMNB1 duplication and features high levels of lamin B1 accumulation in nuclei at the onset of disease, which occurs around the fourth decade 61 . Heterochromatin disorganization and altered import of the transcription factor Oct-1 in nuclei have been reported in ADLD 61 . Of note, Oct-1 sequestering in ADLD muscle nuclei impairs transcription of Myosyn heavy chain 2B, one of the Oct-1 target genes, playing a major role in muscle function 61 .…”