Joint Transnational Call 2009 (JTC2009)


Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a rare, genetic brain disease, clinically characterized by early-onset macrocephaly and after a few years slow deterioration of motor functions, epilepsy and mental decline. In MLC, the cerebral myelin is vacuolated, causing white matter swelling. MLC1 is the first gene demonstrated to be involved in this disease, and it encodes a transmembrane protein of unknown function mainly expressed in astroglial processes. MLC1 mutations reduce MLC1 protein levels. At the beginning of the project, there was no insight into the pathophysiology of MLC and no specific therapy was available. Furthermore, genetic studies had demonstrated that there were other unidentified disease MLC genes.
The general objective of the project was to gain insights into the disease mechanism of MLC in order to find openings for treatment. In order to achieve this objective, we proposed a multidisciplinary approach. Thus, the planned experiments comprise the characterization of animal models of MLC disease (mice and zebrafish, created by inactivation of the MLC1 gene), the analysis of cells with decreased MLC1 expression and a search for new MLC disease genes by genetic linkage or analysis of the MLC1 protein interactome.
We expected that, based on the outcome of the research proposed, we could be able to design screening studies aimed at identifying molecules that could be used for therapy, and they could be tested in our animal models.
With these objectives in mind, our collaborative team identified the second gene of MLC disease, GLIALCAM, which has the role to be a MLC1 subunit, and their interaction is needed for MLC1 proper expression at the membrane in astrocyte-astrocyte junctions. Furthermore, we discovered that in MLC two types of chloride channels are affected. In one hand, GlialCAM had been identified as a ClC-2 auxiliary subunit and in vivo studies in MLC animal models have shown that the chloride channel ClC-2 is mislocalized in astrocytes and oligodendrocytes. On the other hand, electrophysiological measurements from lymphoblast obtained from patients, astrocytes depleted of MLC1 or GlialCAM by RNA interference or astrocytes from the Mlc1-/- mice have shown that the activation of volume-regulated anion currents (VRAC) is impaired. The VRAC activity is involved in cellular osmotic response and failure of its activity may lead to the vacuolization observed in astrocytes.
Thus, we have moved from a lack of knowledge in the pathophysiology of MLC to get the first insights into what physiological process are affected. We envisage that the next years of research in MLC will result in finding exciting molecular details which will allow understanding the exact role of MLC1/GlialCAM in the regulation of chloride fluxes by glial cells and hopefully will provide novel therapies for MLC.

  • Estévez, Raul (Coordinator)
    IDIBELL Ciencias Fisiologiques II [SPAIN]
  • Mansvelder, Huibert
    VU University Medical Center Integrative Neurophysiology [NETHERLANDS]
  • S. Van Der Knaap, Marjo
    VU UNiveristy Medical Center Child Neurology [NETHERLANDS]
  • Verheijen, Mark
    Center for Neurogenomics and Cognitive Research Molecular and Cellular Neurobiology [NETHERLANDS]