EIF2B5 mutations compromise GFAP(+) astrocyte generation in vanishing white matter leukodystrophy

Department of Biomedical Genetics, Aab Institute, University of Rochester School of Medicine and Dentistry, 601 Elmwood Avenue, Rochester, New York 14642, USA.
Nature Medicine (Impact Factor: 28.05). 04/2005; 11(3):277-83. DOI: 10.1038/nm1195
Source: PubMed

ABSTRACT Vanishing white matter disease (VWM) is a heritable leukodystrophy linked to mutations in translation initiation factor 2B (eIF2B). Although the clinical course of this disease has been relatively well described, the cellular consequences of EIF2B mutations on neural cells are unknown. Here we have established cell cultures from the brain of an individual with VWM carrying mutations in subunit 5 of eIF2B (encoded by EIF2B5). Despite the extensive demyelination apparent in this VWM patient, normal-appearing oligodendrocytes were readily generated in vitro. In contrast, few GFAP-expressing (GFAP+) astrocytes were present in primary cultures, induction of astrocytes was severely compromised, and the few astrocytes generated showed abnormal morphologies and antigenic phenotypes. Lesions in vivo also lacked GFAP+ astrocytes. RNAi targeting of EIF2B5 severely compromised the induction of GFAP+ cells from normal human glial progenitors. This raises the possibility that a deficiency in astrocyte function may contribute to the loss of white matter in VWM leukodystrophy.

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    • "A similar situation exists in vanishing white matter disease, a leukodystrophy caused by mutations in subunits of eukaryotic translation initiation factor eIF2B. Unlike Gfap, eIF2B is expressed in all cells, but nonetheless the pathophysiological effects of eIF2B mutations preferentially target white matter tracts resulting in cystic changes associated with extensive demyelination and axonal loss (Dietrich and others 2005). The effector pathways responsible for demyelination and neurodegeneration in these genetic diseases are poorly understood, but circumstantial evidence suggests a role for glutamate-mediated excitotoxicity in Alexander disease. "
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    ABSTRACT: Astrocytes are the most abundant cell type in the adult central nervous system (CNS), and their functional diversity in response to injury is now being appreciated. Astrocytes have long been considered the main player in the inhibition of CNS repair via the formation of the gliotic scar, but now it is accepted that astrocyte can play an important role in CNS repair and remyelination. Interest in the relationship between astrocytes and myelination focused initially on attempts to understand how the development of plaques of astroglial scar tissue in multiple sclerosis was related to the failure of these lesions to remyelinate. It is now considered that this is an end stage pathological response to injury, and that normally astrocytes play important roles in supporting the development and maintenance of CNS myelin. This review will focus on how this new understanding may be exploited to develop new strategies to enhance remyelination in multiple sclerosis and other diseases.
    The Neuroscientist 11/2012; 19(5). DOI:10.1177/1073858412465655 · 7.62 Impact Factor
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    • "The diagnosis of CACH/VWM is based on brain Magnetic Resonance Imaging (MRI) which shows a symmetric and diffuse involvement of the cerebral white matter with a cerebrospinal fluid (CSF)-like intensity signal. The neuropathological features are those of a cavitary leukodystrophy with an increased oligodendrocytic density and reduced number of dystrophic astrocytes (Rodriguez et al., 1999, Wong et al., 2000) due to their abnormal maturation (Dietrich et al., 2005). Mutations in the five genes encoding the five subunits of the eukaryotic initiation factor 2B (eIF2B) have been identified in classical CACH/VWM (Leegwater et al., 2001; van der Knaap et al., 2002; Fogli et al., 2004a; Ohtake et al., 2004; Ohlenbusch et al., 2005) as well as in milder or more severe forms (Fogli et al., 2002; Fogli et al., 2003; van der Knaap et al., 2003; Federico et al., 2006; Mierzewska et al., 2006; Passemard et al., 2007) leading to the definition of eIF2B-related disorders. "
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    ABSTRACT: The CACH/VWM syndrome is an autosomal recessive leukodystrophy characterized by a broad spectrum of clinical presentations and by diffuse cavitary degeneration of the white matter on MRI. Mutations responsible for this disorder are missense or frameshift mutations occurring in the five genes (EIF2B1-5) that encode the translation eukaryotic initiation factor eIF2B. We found that a patient with infantile CACH/VWM carries a mutation in the acceptor splice site of EIF2B5 exon 6. In lymphoblastoid cells of the patient, we detected an abnormal EIF2B5 transcript in which exon 6 was absent, however, the predicted protein product lacking part of the non-catalytic domain encoded by exon 6 was not detected. The eIF2B GEF activity was severely decreased. These data support the importance of the non-catalytic domain of the eIF2Bepsilon subunit in the eIF2B complex formation and activity.
    Annals of Human Genetics 06/2008; 72(Pt 3):410-5. DOI:10.1111/j.1469-1809.2007.00427.x · 1.93 Impact Factor
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    • "Eukaryotic translation elongation factor 1 beta 2 (Barbarese et al. 1995) XP_32044 1 70 Eukaryotic translation initiation factor 2, subunit 2 beta (Dietrich et al. 2005) Q6P685 1 71 Eukaryotic translation factor 1 delta Q68FR9 2 72 Eukaryotic translation initiation factor 3 subunit 5 Q9DCH4 1 73 F-actin capping protein alpha-1 subunit P47753 2 74 F-actin capping protein alpha-2 subunit P47754 2 Fatty acid binding protein, heart P07483 1 d 75 Fatty acid-biding protein, brain P51880 1 76 Fatty acid-binding protein,epidermal (Scarlato et al. 2000) P55053 1 77 Ferritin light chain (Quintana et al. 2006 "
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    ABSTRACT: Oligodendrocytes are glial cells responsible for the synthesis and maintenance of myelin in the central nervous system (CNS). Oligodendrocytes are vulnerable to damage occurring in a variety of neurological diseases. Understanding oligodendrocyte biology is crucial for the dissemination of de- and remyelination mechanisms. The goal of the present study is the construction of a protein database of mature rat oligodendrocytes. Post-mitotic oligodendrocytes were isolated from mature Wistar rats and subjected to immunocytochemistry. Proteins were extracted and analyzed by means of two-dimensional gel electrophoresis and two-dimensional liquid chromatography, both coupled to mass spectrometry. The combination of the gel-based and gel-free approach resulted in confident identification of a total of 200 proteins. A minority of proteins were identified in both proteomic strategies. The identified proteins represent a variety of functional groups, including novel oligodendrocyte proteins. The results of this study emphasize the power of the applied proteomic strategy to study known or to reveal new proteins and to investigate their regulation in oligodendrocytes in different disease models.
    Journal of Neurochemistry 08/2007; 102(2):562-76. DOI:10.1111/j.1471-4159.2007.04575.x · 4.24 Impact Factor
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