SUMMARY

Towards the molecular mechanism of vanishing white matter
Vanishing white matter (VWM) is a leukodystrophy with predominantly early-childhood onset. Affected children display various neurological signs, including ataxia and spasticity, and die early. VWM patients have mutations in the genes encoding the protein complex eukaryotic translation factor 2B (eIF2B). eIF2B regulates protein synthesis rates under basal and cellular stress conditions.
So far research showed that eIF2B activity is reduced by mutations in eIF2B. However, no reduction in protein synthesis was found in cell cultures. The relationship between reduced eIF2B activity and VWM brain pathology remained unclear. Post-mortem brain from VWM patients was found to be positive for some ISR and UPR markers and abnormal activation of the ISR and UPR was suspected as underlying disease mechanism, making patients hypersensitive for further activation of cell stress pathways by stress-inducing factors. Such hypersensitivity could perhaps explain why patients respond with acute and rapid deterioration to external factors as febrile infections. However, such mechanism would not explain the selective involvement of the brain white matter, specifically astrocytes. To explain such selective vulnerability, we needed to find cell-specific changes. We considered that while reduced eIF2B activity may not reduce mRNA translation rates in general, yet may affect the translation rate for specific mRNAs due to mutations in eIF2B.
The goal of the thesis is to improve understanding of molecular disease mechanisms. We reasoned that a further understanding could be improved by open screens that identify and quantify changes in expression of mRNAs and proteins linked to VWM. We profiled genome-wide translational changes in astrocyte cultures and brains of control and mutant mice (chapter 3 and 4). The results from these genome-wide screens are complemented with three studies that aimed to address the stress-sensitive nature of the disease (chapter 2, 5 and 6).