Lamin B1 mediated demyelination: Linking Lamins, Lipids and Leukodystrophies

Abstract

Autosomal Dominant Leukodystrophy (ADLD), a fatal adult onset demyelinating disorder, is the only human disease that has been linked to mutations of the nuclear lamina protein, lamin B1, and is primarily caused by duplications of the LMNB1 gene. Why CNS myelin is specifically targeted and the mechanisms underlying ADLD are unclear. Recent work from our group has demonstrated that over expression of lamin B1 in oligodendrocytes, the myelin producing cells in the CNS, resulted in age dependent epigenetic modifications, transcriptional down-regulation of lipogenic gene expression and significant reductions of myelin-enriched lipids. Given the high lipid content of meylin, we hypothesize that lipid loss is one of the primary drivers of the demyelination phenotype. These results can, at least partially, explain the age dependence and cell type specificity in ADLD and are discussed in the context of the existing literature, in an attempt to delineate potential pathways underlying the disease phenotype.

Keywords: ADLD demyelination; Lamin B1; epigenetic modifications; leukodystrophy; lipid synthesis; nuclear lamina; nuclear structure; transcription.

Figure 1.

Spinal cord degeneration in a mouse model of ADLD. (A) PLP-FLAG-LMNB1 transgenic mice (TG), with oligodendrocyte specific overexpression of lamin B1, show age dependent degenerative phenotypes including kyphosis (black arrow), forelimb paralysis (white arrowhead) and muscle wasting at 13 months while wild type (WT) littermates show no obvious phenotypes. (B) Cervical spinal cords section of TG mice show significant vacuolar degeneration involving the white matter (arrows). No such alterations are observed in spinal cord sections from WT littermates. Top panel – H&E staining, Bottom panel – Fluormyelin staining (Fluromyelin is a fluorescent dye that specifically stains white matter). Reproduced with permission from Rolyan et al., (2015).

Figure 2.

ADLD disease mechanism. Potential disease mechanisms underlying ADLD. Results from our group suggest that lipid dysregulation mediated by age dependent epigenetic alterations in oligodendrocytes are a major driver for the demyelination observed in an ADLD mouse model. However, other pathways such nuclear structural defects or aberrant splicing may also contribute to oligodendrocyte dysfunction. Findings that elevated reactive oxygen species (ROS) promote an accumulation of lamin B1 may provide an alternative hypothesis to explain the late age onset of the disease phenotype.