Lamin B1 mediates cell-autonomous neuropathology in a leukodystrophy mouse model
Mary Y. Heng, … , Louis J. Ptáček, Ying-Hui Fu
Mary Y. Heng, … , Louis J. Ptáček, Ying-Hui Fu
Published May 15, 2013
Citation Information: J Clin Invest. 2013;123(6):2719-2729. https://doi.org/10.1172/JCI66737.
View: Text | PDF
Research Article Neuroscience

Lamin B1 mediates cell-autonomous neuropathology in a leukodystrophy mouse model

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 dysfunction, 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 overexpresses lamin B1. These mice exhibited cognitive impairment and epilepsy, followed by age-dependent motor deficits. Selective overexpression of lamin B1 in oligodendrocytes also resulted in marked motor deficits and myelin defects, suggesting these deficits are cell autonomous. Proteomic and genome-wide transcriptome studies indicated that lamin B1 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 B1 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 B1 overexpression mediates oligodendrocyte cell–autonomous neuropathology in ADLD and implicate lamin B1 as an important regulator of myelin formation and maintenance during aging.

Authors

Mary Y. Heng, Shu-Ting Lin, Laure Verret, Yong Huang, Sherry Kamiya, Quasar S. Padiath, Ying Tong, Jorge J. Palop, Eric J. Huang, Louis J. Ptáček, Ying-Hui Fu

×

Figure 1

Generation of Lmnb1BAC mice.

Options: View larger image (or click on image) Download as PowerPoint
Generation of Lmnb1BAC mice. (A) Map of the genomic insert in the BAC R...
(A) Map of the genomic insert in the BAC RP23-460J18 clone (RPCI library, C57BL/6J) used to generate mice with increased dosage of lamin B1 (Lmnb1BAC mice). The genomic insert is 177.20-kb long and contains the entire Lmnb1 locus. Black boxes represent lamin B1–coding sequences, and light gray lines indicate the BAC vector (pBACe3.6) sequence. Primers used for detection of the transgene are shown (T7 side: F1R1; SP6 side: F2, R2). (B) Representative Western blot of lamin B1 and α-tubulin in hemibrain lysates from Lmnb1BAC lines and WT mice at 12 months of age. (C) Quantification of Western blots normalized to α-tubulin. (D) qRT-PCR of lamin B1 transcript levels normalized to GAPDH from corresponding Lmnb1BAC mice hemibrains. Error bars represent mean ± SEM from 4 independent experiments.