TRANSLATIONAL IMPACT
Clinical issue
Demyelination of the central nervous system (CNS) impairs nervous system function and can create deficits in cognition, sensory perception and movement, depending on the affected brain regions. CNS demyelination can result from a number of genetically characterized, hereditary, childhood- and adult-onset leukodystrophies, the most common disorder being multiple sclerosis (MS).
Little is known about the morphological and molecular changes involved in myelin sheath formation and maintenance. Studies of genetic forms of hypomyelinating and demyelinating leukodystrophies provide unique opportunities to identify the important factors for myelin synthesis, maintenance and (potentially) regeneration. Adult-onset autosomal dominant leukodystrophy (ADLD) is one example where an unexpected structural protein, lamin B1, was found to be important for maintaining normal functional myelin. Lamins are major components of the nuclear envelope that influence transcription factor localization. This study investigates how overexpression of lamin B1 contributes to demyelination in the CNS.
Results
In this paper, the authors use a combination of established cell lines and primary cell culture methods to study the role of lamin B1. Aberrant inner nuclear membrane protein localization and nucleo-cytoplasmic trafficking provide evidence of disrupted nuclear membrane functions. Lamin B1 expression in cells was shown to be crucial for normal oligodendrocyte development and differentiation, and oligodendrocyte development was inhibited with lamin B1 overexpression. Furthermore, they demonstrated that the microRNA miR-23 represses lamin B1 protein levels, contributing to the tight regulation of lamin B throughout development and in adults.
Implications and future directions
The results demonstrate that appropriate regulation of lamin B1 in oligodendrocyte precursor cells and in mature oligodendrocytes is crucial for normal myelin maintenance. This suggests that therapeutic interventions that reduce lamin B1 might be a potential treatment for ADLD patients. As the molecular mechanisms of myelin synthesis and maintenance are further defined, proteins and microRNAs that are important for these processes can be investigated as potential drug targets for the prevention of myelin degeneration and/or to assist in myelin maintenance.
