Abstract
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.
Highlights
Compact concentric wraps of myelin, a unique characteristic of vertebrates, can speed up propagation of electrical activities along axons in the nervous system
We address adult onset autosomal dominant leukodystrophy (ADLD), recently shown to be caused by increased expression of lamin B1 resulting from duplication of the gene encoding lamin B1, lamin B1 gene (LMNB1) [18,19,20,21,22,23,24], or possibly its dysregulation [25]
The adverse effect of LMNB1 overexpression in oligodendrocytes can be abrogated by miR-23, suggesting that it may be a negative regulator of lamin B1 [26]
Summary
Compact concentric wraps of myelin, a unique characteristic of vertebrates, can speed up propagation of electrical activities along axons in the nervous system. Supporting in vivo findings, in a primary culture system, transient overexpression of lamin B1 in oligodendrocytes by lentiviral transduction causes defects in myelin protein expression and differentiation accompanied by mild nuclear envelope growth/distortion [26] Overall, these results indicate that overexpression of lamin B1 could disturb the unique gene expression patterns in individual CNS cell types and that these phenotypes would only appear in certain cell types that are vulnerable to transcriptional perturbance during differentiation. These results indicate that overexpression of lamin B1 could disturb the unique gene expression patterns in individual CNS cell types and that these phenotypes would only appear in certain cell types that are vulnerable to transcriptional perturbance during differentiation These studies identify a mechanism by which excessive lamin B1 expression can cause oligodendrocyte cell-autonomous neuropathology in ADLD, and implicate lamin B1 as an important factor for myelin formation and maintenance. These findings further highlight the complexity of oligodendrocyte/myelin regulatory pathways, as demonstrated by the coordination of transcriptional (transcription factors) and post-transcriptional (miRNA and lncRNA) mechanisms
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