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- Title
Lamin B1 mediates cell-autonomous neuropathology in a leukodystrophy mouse model.
- Authors
Heng, Mary Y.; Lin, Shu-Ting; Verret, Laure; Yong Huang; Kamiya, Sherry; Padiath, Quasar S.; Ying Tong; Palop, Jorge J.; Huang, Eric J.; Ptacek, Louis J.; Fu, Ying-Hui
- Abstract
Adult-onset autosomal-dominant leukodystrophy (ADLD) is a progressive and fatal neurological disorder characterized by early autonomic dysfunction, cognitive impairment, pyramidal tract and cerebellar dysfunc-tion, and white matter loss in the central nervous system. ADLD is caused by duplication of the LMNB1 gene, which results in increased lamin B1 transcripts and protein expression. How duplication of LMNB1 leads to myelin defects is unknown. To address this question, we developed a mouse model of ADLD that overex-presses lamin Bl. These mice exhibited cognitive impairment and epilepsy, followed by age-dependent motor deficits. Selective overexpression of lamin Bl in oligodendrocytes also resulted in marked motor deficits and myelin defects, suggesting these deficits are cell autonomous. Proteomic and genome-wide transcriptome stud-ies indicated that lamin Bl overexpression is associated with downregulation of proteolipid protein, a highly abundant myelin sheath component that was previously linked to another myelin-related disorder, Pelizaeus-Merzbacher disease. Furthermore, we found that lamin Bl overexpression leads to reduced occupancy of Yin Yang 1 transcription factor at the promoter region of proteolipid protein. These studies identify a mechanism by which lamin Bl overexpression mediates oligodendrocyte cell-autonomous neuropathology in ADLD and implicate lamin Bl as an important regulator of myelin formation and maintenance during aging.
- Subjects
NEUROLOGICAL disorders; LAMINS; LEUKODYSTROPHY; FETAL diseases; DYSAUTONOMIA; COGNITION disorders; LABORATORY mice
- Publication
Journal of Clinical Investigation, 2013, Vol 123, Issue 6, p2719
- ISSN
0021-9738
- Publication type
Article
- DOI
10.1172/JCI66737