[show abstract][hide abstract] 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.
[show abstract][hide abstract] ABSTRACT: VLGR1 (very large G protein-coupled receptor 1), also known as MASS1 (monogenic audiogenic seizure susceptible 1), is an orphan G protein-coupled receptor that contains a large extracellular N terminus with 35 calcium-binding domains. A truncating mutation in the Mass1 gene causes autosomal recessive, sound-induced seizures in the Frings mouse. However, the function of MASS1 and the mechanism underlying Frings mouse epilepsy are not known. Here, we found that MASS1 protein is enriched in the myelinated regions of the superior and inferior colliculi, critical areas for the initiation and propagation of audiogenic seizures. Using a panel of myelin antibodies, we discovered that myelin-associated glycoprotein (MAG) expression is dramatically decreased in Frings mice. MASS1 inhibits the ubiquitylation of MAG, thus enhancing the stability of this protein, and the calcium-binding domains of MASS1 are essential for this regulation. Furthermore, MASS1 interacts with Gαs/Gαq and activates PKA and PKC in response to extracellular calcium. Suppression of signaling by MASS1 RNAi or a specific inhibitor abrogates MAG up-regulation. We postulate that MASS1 senses extracellular calcium and activates cytosolic PKA/PKC pathways to regulate myelination by means of MAG protein stability in myelin-forming cells of the auditory pathway. Further work is required to determine whether MAG dysregulation is a cause or consequence of audiogenic epilepsy and whether there are other pathways regulated by MASS1.
Proceedings of the National Academy of Sciences 11/2013; · 9.74 Impact Factor
[show abstract][hide abstract] ABSTRACT: 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.
Proceedings of the National Academy of Sciences 10/2013; · 9.74 Impact Factor
[show abstract][hide abstract] ABSTRACT: 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.
The Journal of clinical investigation 05/2013; · 15.39 Impact Factor
[show abstract][hide abstract] ABSTRACT: Temporally restricted feeding (RF) can phase reset the circadian clocks in numerous tissues in mammals, contributing to altered timing of behavioral and physiological rhythms. However, little is known regarding the underlying molecular mechanism. Here we demonstrate a role for the gamma isotype of protein kinase C (PKCγ) in food-mediated entrainment of behavior and the molecular clock. We found that daytime RF reduced late-night activity in wild-type mice but not mice homozygous for a null mutation of PKCγ (PKCγ(-/-)). Molecular analysis revealed that PKCγ exhibited RF-induced changes in activation patterns in the cerebral cortex and that RF failed to substantially phase shift the oscillation of clock gene transcripts in the absence of PKCγ. PKCγ exerts effects on the clock, at least in part, by stabilizing the core clock component brain and muscle aryl hydrocarbon receptor nuclear translocator like 1 (BMAL1) and reducing its ubiquitylation in a deubiquitination-dependent manner. Taken together, these results suggest that PKCγ plays a role in food entrainment by regulating BMAL1 stability.
Proceedings of the National Academy of Sciences 11/2012; · 9.74 Impact Factor
[show abstract][hide abstract] ABSTRACT: Duplication of the gene encoding lamin B1 (LMNB1) with increased mRNA and protein levels has been shown to cause severe myelin loss in the brains of adult-onset autosomal dominant leukodystrophy patients. Similar to many neurodegenerative disorders, patients with adult-onset autosomal dominant leukodystrophy are phenotypically normal until adulthood and the defect is specific to the central nervous system despite the ubiquitous expression pattern of lamin B1. We set out to dissect the molecular mechanisms underlying this demyelinating phenotype. Increased lamin B1 expression results in disturbances of inner nuclear membrane proteins, chromatin organization and nuclear pore transport in vitro. It also leads to premature arrest of oligodendrocyte differentiation, which might be caused by reduced transcription of myelin genes and by mislocalization of myelin proteins. We identified the microRNA miR-23 as a negative regulator of lamin B1 that can ameliorate the consequences of excessive lamin B1 at the cellular level. Our results indicate that regulation of lamin B1 is important for myelin maintenance and that miR-23 contributes to this process, at least in part, by downregulating lamin B1, therefore establishing novel functions of lamin B1 and miR-23 in the regulation of oligodendroglia development and myelin formation in vitro.
Disease Models and Mechanisms 01/2009; 2(3-4):178-88. · 4.96 Impact Factor