Adult-onset autosomal dominant leukodystrophy (ADLD) is a progressive and fatal hereditary demyelination disorder characterized initially by autonomic dysfunction and loss of myelin in the central nervous system (CNS). Majority of ADLD is caused by a genomic duplication of the nuclear lamin B1 gene (LMNB1) encoding lamin B1 protein, resulting in increased gene dosage in brain tissue. In vitro, excessive lamin B1 at the cellular level reduces transcription of myelin genes, leading to premature arrest of oligodendrocyte differentiation. Murine models of ADLD overexpressing LMNB1 exhibited age-dependent motor deficits and myelin defects, which are associated with reduced occupancy of the Yin Yang 1 transcription factor at the promoter region of the proteolipid protein gene. Lamin B1 overexpression mediates oligodendrocyte cell-autonomous neuropathology in ADLD and suggests lamin B1 as an important regulator of myelin formation and maintenance during aging. Identification of microRNA-23 (miR-23) as a negative regulator of lamin B1 can ameliorate the consequences of excessive lamin B1 at the cellular level. miR-23a-overexpressing mice display enhanced oligodendrocyte differentiation and myelin synthesis. miR-23a targets include a protein coding transcript PTEN (phosphatase and tensin homolog on chromosome 10), and a long noncoding RNA (2700046G09Rik), indicating a unique role for miR-23a in the coordination of proteins and noncoding RNAs in generating and maintaining healthy myelin. Here, we provide a concise review of the current literature on clinical presentations of ADLD and how lamin B1 affects myelination and other developmental processes. Moreover, we address the emerging role of non-coding RNAs (ncRNAs) in modulating gene networks, specifically investigating miR-23 as a potential target for the treatment of ADLD and other demyelinating disorders.

Demyelinating disorders including leukodystrophies are devastating conditions that are still in need of better understanding, and both oligodendrocyte differentiation and myelin synthesis pathways are potential avenues for developing treatment. Overexpression of lamin B1 leads to leukodystrophy characterized by demyelination of the central nervous system, and microRNA-23 (miR-23) was found to suppress lamin B1 and enhance oligodendrocyte differentiation in vitro. Here, we demonstrated that miR-23a-overexpressing mice have increased myelin thickness, providing in vivo evidence that miR-23a enhances both oligodendrocyte differentiation and myelin synthesis. Using this mouse model, we explored possible miR-23a targets and revealed that the phosphatase and tensin homologue/phosphatidylinositol trisphosphate kinase/Akt/mammalian target of rapamycin pathway is modulated by miR-23a. Additionally, a long noncoding RNA, 2700046G09Rik, was identified as a miR-23a target and modulates phosphatase and tensin homologue itself in a miR-23a-dependent manner. The data presented here imply a unique role for miR-23a in the coordination of proteins and noncoding RNAs in generating and maintaining healthy myelin.

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.

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.