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.