MLC1 is associated with the Dystrophin-Glycoprotein Complex at astrocytic endfeet

Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a progressive cerebral white matter disease with onset in childhood, caused by mutations in the MLC1 gene. MLC1 is a protein with unknown function that is mainly expressed in the brain in astrocytic endfeet at the blood–brain and cerebrospinal fluid–brain barriers. It shares its localization at astrocytic endfeet with the dystrophin-associated glycoprotein complex (DGC). The objective of the present study was to investigate the possible association of MLC1 with the DGC. To test this hypothesis, (co)-localization of DGC-proteins and MLC1 was analyzed by immunohistochemical stainings in gliotic brain tissue from a patient with multiple sclerosis, in glioblastoma tissue and in brain tissue from an MLC patient. In control tissue, a direct protein interaction was tested by immunoprecipitation. Results revealed that MLC1 is co-localized with DGC-proteins in gliotic brain tissue. We demonstrated that both MLC1 and aquaporin-4, a member of the DGC, were redistributed in glioblastoma cells. In MLC brain tissue, we showed absence of MLC1 and altered expression of several DGC-proteins. We demonstrated a direct protein interaction between MLC1 and Kir4.1. From these results we conclude that MLC1 is associated with the DGC at astrocytic endfeet

Vanishing white matter disease

Vanishing white matter disease (VWM) is one of the most prevalent inherited childhood leucoencephalopathies. The classical phenotype is characterised by early childhood onset of chronic neurological deterioration, dominated by cerebellar ataxia. VWM is unusual because of its clinically evident sensitivity to febrile infections, minor head trauma, and acute fright, which may cause rapid neurological deterioration and unexplained coma. Most patients die a few years after onset. The phenotypic variation is extremely wide, including antenatal onset and early demise and adult-onset, slowly progressive disease. MRI findings are diagnostic in almost all patients and are indicative of vanishing of the cerebral white matter. The basic defect of this striking disease resides in either one of the five subunits of eukaryotic translation initiation factor eIF2B. eIF2B is essential in all cells of the body for protein synthesis and its regulation under different stress conditions. Although the defect is in housekeeping genes, oligodendrocytes and astrocytes are predominantly affected, whereas other cell types are surprisingly spared. Recently, undue activation of the unfolded-protein response has emerged as important in the pathophysiology of VWM, but the selective vulnerability of glia for defects in eIF2B is poorly understood

Defective translation initiation causes vanishing of cerebral white matter

Leukoencephalopathy with vanishing white matter (VWM) is one of the most prevalent inherited white-matter disorders, especially in Caucasian populations. VWM is unusual because of its sensitivity to febrile infections and minor head trauma. The basic defect of this enigmatic brain disease resides in the regulation of initiation of protein synthesis. Recently, undue activation of the unfolded-protein response has emerged as an important factor in the pathophysiology of VWM. Here, we discuss the mechanisms that might be responsible for the selective involvement of the brain white matter in VWM. At present, VWM research is in need of an animal model to study disease mechanisms and therapeutic interventions

Vanishing white matter disease: A review with focus on its genetics

Leukoencephalopathy with vanishing white matter (VWM) is an autosomal recessive brain disorder, most often with a childhood onset. Magnetic resonance imaging and spectroscopy indicate that, with time, increasing amounts of cerebral white matter vanish and are replaced by fluid. Autopsy confirms white matter rarefaction and cystic degeneration. The process of localization and identification of the first two genes related to VWM, EIF2B5 and EIF2B2, was facilitated by two founder effects in the Dutch population. EIF2B5 and EIF2B2 encode the ε and β subunits of translation initiation factor eIF2B. Soon it was shown that mutations in all five eIF2B subunit genes can cause VWM. EIF2B is essential for the initiation of translation of RNA into protein and is involved in regulation of the process, especially under stress conditions, which may explain the sensitivity to stress conditions observed in VWM patients. The pathophysiology of the disease is still poorly understood

Vanishing white matter disease: the first reported chinese patient

Vanishing white matter disease is a rare neurological disease. The majority of patients reported are Caucasian individuals. We describe the first Chinese patient with typical clinical and radiological features genetically confirmed to have vanishing white matter disease for a mutation in EIF2B4, followed by a brief review of the diseas

Nerve and epidermal growth factor induce protein synthesis and eIF2B activation in PC12 cells

The regulation of protein synthesis and of eukaryotic initiation factor eIF2B was studied in PC12 cells. An increase in protein synthesis was observed after nerve growth factor (NGF) and epidermal growth a factor (EGF) treatment of PC12 cells, and this increase coincided with activation of eIF2B. Growth factor addition in the presence of the phosphatidylinositol-3'-OH kinase inhibitor wortmannin showed that both NGF- and EGF-induced protein synthesis and eIF2B activation were phosphatidylinasitol-3'-OH kinase dependent. The EGF-induced stimulation of protein synthesis and activation of eIF2B was dependent upon FK506-binding protein-rapamycin-associated protein, as shown with the immunosuppressant rapamycin, whereas NGF induction was partially dependent upon FK506-bindinag protein-rapamycin-associated protein. The activities of two kinases that act on eIF2B, glycogen synthase kinase-3 and casein kinase II, were measured to assess their potential roles in the activation of eIF2B in PC12 cells. inactivation of glycogen synthase kinase-3 was seen in response to both NGF and EGF and this coincided with activation of eIF2B. However, inactivation of glycogen synthase kinase-3 was not rapamycin sensitive, in contrast to the activation of eIF2B. This indicates the involvement of another protein kinase or regulatory mechanism in the eIF2B activation. Both growth factors activated casein kinase II. However, the time course of its activation and its insensitivity to wortmannin and rapamycin suggest that casein kinase II does not play a major regulatory role in eIF2B activation under these conditions