Marjo van der Knaap (principal investigator), Gert Scheper and Peter Heutink receive a prestigious TOP grant from ZonMw. ZonMw’s TOP program is designed to create scope for major scientific initiatives. The budget is approximately € 650k per grant. The project title is “White matter disorders in children: from magnetic resonance to basic defect and treatment”. The focus of the research on childhood brain white matter disorders of the Neuroscience Campus Amsterdam is on unclassified childhood disorders. Novel diseases are defined by their distinct pattern of Magnetic Resonance Imaging (MRI) abnormalities. Subsequently, a search is started for the related disease genes. Identification of a disease gene is followed by studies on disease mechanisms, in particular to find openings for treatment. This line of research has been extremely successful and has led to the definition of several disorders, including Vanishing White Matter disease (VWM) and Megalencephalic Leukoencephalopathy with subcortical Cysts (MLC).
The TOP grant goes to two specific projects.
1.Genetic studies. We receive 800-1000 MRI second opinions on unclassified leukoencephalopathies per year. With these high numbers we can identify extremely rare disorders of which we only know a few patients. The family data are insufficient for genetic linkage. With funding of the ZonMw grant we will apply whole exome analysis by massive parallel sequencing, also known as next generation sequencing, to find the related genes.
2.Disease mechanisms of VWM. We have found the five genes for VWM in 2001. We have acquired increasing insights into brain pathology and pathophysiology, but our findings have not closed the gap between genetic defect and detrimental activation of certain pathways and the selective involvement of oligodendrocytes and astrocytes. With the ZonMw funding we will address this subject. The genes that are mutated in VWM encode proteins that form the complex eIF2B, which is involved in regulation of protein synthesis. We will follow two complementary approaches, ribosomal profiling and pulsed SILAC, to identify proteins of which the synthesis is directly affected by mutations in subunits of eIF2B. We will use cells from the newly developed VWM mouse models as well as cultured cells treated with small interfering RNAs to reduce expression of relevant genes. We expect that insight into the proteins that have an altered expression in VWM will increase our understanding of the mechanism by which a defect in eIF2B leads to a disease that primarily affects oligodendrocytes and astrocytes.