Journal
NUCLEUS
Volume 7, Issue 6, Pages 547-553Publisher
TAYLOR & FRANCIS INC
DOI: 10.1080/19491034.2016.1260799
Keywords
ADLD demyelination; epigenetic modifications; lipid synthesis; leukodystrophy; Lamin B1; nuclear lamina; nuclear structure; transcription
Categories
Funding
- National Institutes of Health [R01NS095884, R21AG046897]
- National Multiple Sclerosis Society Grant [RG5045A1]
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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.
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