title: 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.
  
  
  CONCLUSIONS
  Autosomal 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.
authors: Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania 15216.
authors: Harshvardhan
authors: H
authors: Rolyan
authors: Center for Free Radical and Antioxidant Health, Department of Environmental and Occupational Health, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania 15219.
authors: Yulia Y
authors: YY
authors: Tyurina
authors: Friedman Brain Institute Center for Neural Repair, Department of Neuroscience, and Graduate School of Biological Sciences, The Icahn School of Medicine at Mount Sinai, New York, New York 10029.
authors: Marylens
authors: M
authors: Hernandez
authors: Center for Free Radical and Antioxidant Health, Department of Environmental and Occupational Health, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania 15219.
authors: Andrew A
authors: AA
authors: Amoscato
authors: Center for Free Radical and Antioxidant Health, Department of Environmental and Occupational Health, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania 15219.
authors: Louis J
authors: http://orcid.org/0000-0001-6347-8448
authors: LJ
authors: Sparvero
authors: Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania 15216.
authors: Bruce C
authors: BC
authors: Nmezi
authors: Department of Epigenetics and Molecular Carcinogenesis, and Center for Cancer Epigenetics, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030.
authors: Yue
authors: Y
authors: Lu
authors: Department of Epigenetics and Molecular Carcinogenesis, and Center for Cancer Epigenetics, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030.
authors: Marcos R H
authors: MR
authors: Estécio
authors: Department of Epigenetics and Molecular Carcinogenesis, and Center for Cancer Epigenetics, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030.
authors: Kevin
authors: K
authors: Lin
authors: Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania 15216.
authors: Junda
authors: J
authors: Chen
authors: Center for Free Radical and Antioxidant Health, Department of Environmental and Occupational Health, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania 15219.
authors: Rong-Rong
authors: RR
authors: He
authors: Center for Free Radical and Antioxidant Health, Department of Environmental and Occupational Health, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania 15219.
authors: Pin
authors: P
authors: Gong
authors: Division of Laboratory Animal Resources, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261.
authors: Lora H
authors: LH
authors: Rigatti
authors: Department of Anatomy and Neurobiology, Virginia Commonwealth University, Richmond, Virginia 23298, and.
authors: Jeffrey
authors: J
authors: Dupree
authors: Center for Free Radical and Antioxidant Health, Department of Environmental and Occupational Health, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania 15219, Safar Center for Resuscitation Research and Departments of Critical Care Medicine.
authors: Hülya
authors: H
authors: Bayır
authors: Center for Free Radical and Antioxidant Health, Department of Environmental and Occupational Health, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania 15219, Pharmacology and Chemical Biology, Chemistry, and Radiation Oncology, University of Pittsburgh, Pittsburgh, Pennsylvania 15219.
authors: Valerian E
authors: VE
authors: Kagan
authors: Graduate School of Biological Sciences, The Icahn School of Medicine at Mount Sinai, New York, New York 10029.
authors: Patrizia
authors: http://orcid.org/0000-0002-4785-9264
authors: P
authors: Casaccia
authors: Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania 15216, qpadiath@pitt.edu.
authors: Quasar S
authors: QS
authors: Padiath
mesh_terms: D000375:Aging / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D003711:Demyelinating Diseases / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D034921:Lamin Type B / Q000096:biosynthesis*; D050356:Lipid Metabolism / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D034881:Nuclear Lamina / Q000235:genetics / Q000378:metabolism; D009836:Oligodendroglia / Q000378:metabolism
chemical_list: D034921:Lamin Type B
keywords: Lamin B1; chromatin; demyelination; gene expression; inflammation; lipid