Lamin B1 mediates cell-autonomous neuropathology in a leukodystrophymouse model

摘要

Adult-onset autosomal-dominant leukodystrophy (ADLD) is a progressive and fatalneurological disorder characterized by early autonomic dysfunction, cognitiveimpairment, pyramidal tract and cerebellar dysfunction, and white matter loss in thecentral nervous system. ADLD is caused by duplication of the LMNB1 gene, which results in increased lamin B1 transcripts and protein expression. Howduplication of LMNB1 leads to myelin defects is unknown. To addressthis question, we developed a mouse model of ADLD that overexpresses lamin B1. Thesemice exhibited cognitive impairment and epilepsy, followed by age-dependent motordeficits. Selective overexpression of lamin B1 in oligodendrocytes also resulted inmarked motor deficits and myelin defects, suggesting these deficits are cellautonomous. Proteomic and genome-wide transcriptome studies indicated that lamin B1overexpression is associated with downregulation of proteolipid protein, a highlyabundant myelin sheath component that was previously linked to another myelin-relateddisorder, Pelizaeus-Merzbacher disease. Furthermore, we found that lamin B1overexpression leads to reduced occupancy of Yin Yang 1 transcription factor at thepromoter region of proteolipid protein. These studies identify a mechanism by whichlamin B1 overexpression mediates oligodendrocyte cell–autonomousneuropathology in ADLD and implicate lamin B1 as an important regulator of myelinformation and maintenance during aging.