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 leukodys-trophy (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 patho-genesis and may also shed light on the regulation of lipid synthesis pathways in myelin maintenance and turnover.
Original language | English (US) |
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Pages (from-to) | 2002-12017 |
Number of pages | 10016 |
Journal | Journal of Neuroscience |
Volume | 35 |
Issue number | 34 |
DOIs | |
State | Published - Aug 26 2015 |
Keywords
- Chromatin
- Demyelination
- Gene expression
- Inflammation
- Lamin B1
- Lipid
ASJC Scopus subject areas
- General Neuroscience
MD Anderson CCSG core facilities
- Advanced Technology Genomics Core