Defects of Lipid Synthesis Are Linked to the Age-Dependent Demyelination Caused by Lamin B1 Overexpression

Abstract

Lamin B1 is a component of the nuclear lamina and plays a critical role in maintaining nuclear architecture, regulating gene expression and modulating chromatin positioning. We have previously shown that LMNB1 gene duplications cause autosomal dominant leukodystrophy (ADLD), a fatal adult onset demyelinating disease. The mechanisms by which increased LMNB1 levels cause ADLD are unclear. To address this, we used a transgenic mouse model where Lamin B1 overexpression is targeted to oligodendrocytes. These mice showed severe vacuolar degeneration of the spinal cord white matter together with marked astrogliosis, microglial infiltration, and secondary axonal damage. Oligodendrocytes in the transgenic mice revealed alterations in histone modifications favoring a transcriptionally repressed state. Chromatin changes were accompanied by reduced expression of genes involved in lipid synthesis pathways, many of which are known to play important roles in myelin regulation and are preferentially expressed in oligodendrocytes. Decreased lipogenic gene expression resulted in a significant reduction in multiple classes of lipids involved in myelin formation. Many of these gene expression changes and lipid alterations were observed even before the onset of the phenotype, suggesting a causal role. Our findings establish, for the first time, a link between LMNB1 and lipid synthesis in oligodendrocytes, and provide a mechanistic framework to explain the age dependence and white matter involvement of the disease phenotype. These results have implications for disease pathogenesis and may also shed light on the regulation of lipid synthesis pathways in myelin maintenance and turnover. Key words: chromatin; demyelination; gene expression; inflammation; Lamin B1; lipid Significance StatementAutosomal dominant leukodystrophy (ADLD) is fatal neurological disorder caused by increased levels of the nuclear protein, Lamin B1. The disease is characterized by an age-dependent loss of myelin, the fatty sheath that covers nerve fibers. We have studied a mouse model where Lamin B1 level are increased in oligodendrocytes, the cell type that produces myelin in the CNS. We demonstrate that destruction of myelin in the spinal cord is responsible for the degenerative phenotype in our mouse model. We show that this degeneration is mediated by reduced expression of lipid synthesis genes and the subsequent reduction in myelin enriched lipids. These findings provide a mechanistic framework to explain the age dependence and tissue specificity of the ADLD disease phenotype.

Lamin B1 mediated demyelination: Linking Lamins, Lipids and Leukodystrophies

“…As predicted from the histone alterations, there was a dramatic increase in the percentage of genes that were down regulated in the older TG mice from 8.4% (3 months) to 48.4% (13 months) suggesting that the chromatin alterations do indeed lead to a global transcriptional repression in an age dependent manner. 19 Up regulated genes primarily belonged to inflammatory pathways and were thought to indicate a secondary response to the demyelination phenotype derived from astrocytes or microglia. Only 12 genes that were common to the 2 time points were downregulated.…”

“…To further understand these mechanisms, our group, in a report by Rolyan et al (2015) characterized independently derived mouse lines that expressed a FLAG tagged lamin B1 in oligodendrocytes. 19 These FLAG-PLP-LMNB1 transgenic (TG) mice exhibited a robust overexpression of lamin B1 that was highest in the spinal cord and an age dependent muscle wasting, kyphosis and motor dysfunction that culminated in premature mortality by 13-15 months of age (Fig.…”

“…19 These FLAG-PLP-LMNB1 transgenic (TG) mice exhibited a robust overexpression of lamin B1 that was highest in the spinal cord and an age dependent muscle wasting, kyphosis and motor dysfunction that culminated in premature mortality by 13-15 months of age (Fig. 1a).…”

“…Another similarity was the finding that in ADLD patents axonal loss was minimal while in the mice axonal loss was present only in the terminal stages, secondary to the demyelination. 19,20 Some differences were also present between the mouse model and human disease. The mouse model showed significant astrocytosis and microglial infiltration, with some degree of microglial infiltration present even before the onset of demyelination in the mice.…”

“…The PLP-FLAG-LMNB1 mouse model displayed the most severe pathology in the spinal cord while other regions such as the brain stem showed minimal involvement. 19 In ADLD patients, in addition to the spinal cord, the brain stem, cerebellum and cerebral lobes all show white matter loss. 20,21 We attributed this difference to the expression pattern of the transgenic FLAG tagged LMNB1 protein which was maximal in the spinal cord.…”