Abstract
The nuclear lamina is a fibrous meshwork of proteins found adjacent to the inner nuclear membrane that plays a critical role in the maintenance of nuclear architecture. Made up of A and B type lamins, the nuclear lamina has recently been shown to contribute to numerous cellular functions such as chromatin organization, DNA replication, cellular proliferation, senescence, and aging. While at least a dozen disorders are associated with LMNA, the focus of this review is Autosomal Dominant Leukodystrophy (ADLD), the only disease associated with the lamin B1 gene (LMNB1). ADLD is a fatal, adult onset CNS demyelinating disorder that is caused by either genomic duplications involving LMNB1 or deletions upstream of the gene. Both mutation types result in increased LMNB1 gene expression. How the increased levels of this widely expressed nuclear structural component results a phenotype as specific as demyelination is a great mystery. This review summarizes what is currently known about the disease and describes recent work using animal and cell culture models that have provided critical insights into ADLD pathological mechanisms. The delineation of these pathways provides a fascinating glimpse into entirely novel roles for the nuclear lamina and will be critical for the identification of therapies for this fatal disease.
Highlights
The development of multiple mouse and cell culture models have contributed significant insights into the pathogenesis of ADLD and provided tantalizing clues as to how a widely expressed protein such as Lamin B1 can be involved in a specific pathology such as demyelination (Table 1)
This is important for understanding the basic biology of the ADLD but will be critical in identifying therapeutic interventions for this fatal disorder
Summary
The nuclear lamina is a fibrous meshwork of intermediate filament proteins that is found adjacent to the inner nuclear envelope (Tatli and Medalia, 2018). Identified as a structural component critical for the maintaining the architecture of the nucleus, the nuclear lamina is known to be involved in a diverse array of cellular and organismal processes. These include roles in cellular proliferation, senescence, aging, DNA replication and the 3D positioning of chromatin within the nucleus (Gruenbaum and Foisner, 2015; van Steensel and Belmont, 2017). The A type lamins, lamin A and C are splice isoforms encoded for by a single gene LMNA. The only disease associated with lamin B1, the focus of this review, is the fatal neurological disorder Autosomal Dominant Leukodystrophy (ADLD) (Padiath et al, 2006)
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