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
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