Demyelinating and dysmyelinating disorders include a large number of degenerative conditions in humans including Multiple Sclerosis. Recently, myelin involvement in psychiatric disorders such as schizophrenia was also suggested. Understanding how myelin is synthesized and properly maintained is a challenging task that has been under intense investigation for decades. However, our knowledge of these processes is still limited and effective treatments for most of the demyelinating/dysmyelinating diseases are absent. Adult-onset autosomal dominant leukodystrophy (ADLD) is a slowly progressive, neurological disorder characterized by symmetrical widespread myelin loss in the CNS, with a phenotype similar to chronic progressive multiple sclerosis (MS). We have recently identified a genomic duplication that causes ADLD. Patients carry an extra copy of the gene for the nuclear lamina protein, Lamin B1, resulting in increased gene dosage in ADLD brain tissue. Increased expression of Lamin B1 in Drosophila resulted in a degenerative phenotype. In addition, an abnormal nuclear morphology was apparent when cultured cells over-expressed this protein. This is the first human disease attributable to Lamin B1 mutations. Antibodies to Lamin B are found in autoimmune diseases and it is also an antigen recognized by a monoclonal antibody, J1-31, raised against plaques dissected from MS patient brains. This raises the possibility that it may be linked to the autoimmune attack that occurs in MS. In this grant, we propose to study the expression pattern and regulation of Lamin B1 to lay a foundation for future investigation into the mechanism by which Lamin B1 regulates proper myelin maintenance. We have generated BAC and cDNA transgenic mouse models that express less than four extra copies of LMNB1 genes. We are also in the process of generating conditional (under tet regulation) overexpression mouse models. Characterization of these mice will provide insight into the mechanisms not only for ADLD pathophysiology but also for myelin biogenesis. In addition, we identified miR-23 as a negative regulator of Lamin B1. We propose to use primary culture and co-culture methods to study the effect of Lamin B1 and miR-23 in oligodendrocyte development and myelination. Such knowledge will yield insights into pathways through which Lamin B1 overexpression leads to demyelination. Understanding the mechanism of this demyelinating disorder may provide clues to pathways that modulate the expression of acquired leukodystrophies. Ultimately, this knowledge will provide new insight in the synthesis and maintenance of myelin and identify novel targets for developing therapeutic interventions for stimulating remyelination in common disorders like MS.

Public Health Relevance

Disorders of myelin are devastating conditions with limited treatment options. Studies of the demyelinating mechanisms caused by genetic disorders will provide new knowledge into the process of myelin synthesis and maintenance. This knowledge will be important for developing more effective therapeutic intervention for diseases of white-matter.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS062733-02
Application #
7897872
Study Section
Cellular and Molecular Biology of Glia Study Section (CMBG)
Program Officer
Tagle, Danilo A
Project Start
2009-07-20
Project End
2011-06-30
Budget Start
2010-07-01
Budget End
2011-06-30
Support Year
2
Fiscal Year
2010
Total Cost
$424,875
Indirect Cost
Name
University of California San Francisco
Department
Neurology
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Heng, Mary Y; Lin, Shu-Ting; Verret, Laure et al. (2013) Lamin B1 mediates cell-autonomous neuropathology in a leukodystrophy mouse model. J Clin Invest 123:2719-29
Lin, Shu-Ting; Huang, Yong; Zhang, Luoying et al. (2013) MicroRNA-23a promotes myelination in the central nervous system. Proc Natl Acad Sci U S A 110:17468-73
Shin, D; Howng, S Y B; Ptá?ek, L J et al. (2012) miR-32 and its target SLC45A3 regulate the lipid metabolism of oligodendrocytes and myelin. Neuroscience 213:29-37
Lin, Shu-Ting; Ptácek, Louis J; Fu, Ying-Hui (2011) Adult-onset autosomal dominant leukodystrophy: linking nuclear envelope to myelin. J Neurosci 31:1163-6
Padiath, Quasar Saleem; Fu, Ying-Hui (2010) Autosomal dominant leukodystrophy caused by lamin B1 duplications a clinical and molecular case study of altered nuclear function and disease. Methods Cell Biol 98:337-57
Shin, Daesung; Shin, Ji-Yeon; McManus, Michael T et al. (2009) Dicer ablation in oligodendrocytes provokes neuronal impairment in mice. Ann Neurol 66:843-57