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Journal of Neuropathology & Experimental Neurology:
doi: 10.1097/01.jnen.0000228201.27539.50
Original Articles

Glia-Specific Activation of All Pathways of the Unfolded Protein Response in Vanishing White Matter Disease

van Kollenburg, Barbara MSc; van Dijk, Jantine MSc; Garbern, James MD, PhD; Thomas, Adri A. M. PhD; Scheper, Gert C. PhD; Powers, James M. MD; van der Knaap, Marjo S. MD, PhD

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Abstract

Leukoencephalopathy with vanishing white matter (VWM) is a childhood white matter disorder with an autosomal-recessive mode of inheritance. The clinical course is chronic progressive with episodes of rapid neurologic deterioration after febrile infections. The disease is caused by mutations in the genes encoding the subunits of eukaryotic initiation factor 2B (eIF2B), a protein complex that is essential for protein synthesis. In VWM, mutations in the eIF2B genes are thought to impair the ability of cells to regulate protein synthesis under normal and stress conditions. It has been suggested that the pathophysiology of VWM involves inappropriate activation of the unfolded protein response (UPR). The UPR is a protective mechanism activated by an overload of unfolded or malfolded proteins in the endoplasmic reticulum. Activation of one pathway of the UPR, in which eIF2B is involved, has already been described in brain tissue of patients with VWM. In the present study, we demonstrate activation of all 3 UPR pathways in VWM brain tissue using real-time quantitative polymerase chain reaction and immunohistochemistry. We show that activation occurs exclusively in the white matter, predominantly in oligodendrocytes and astrocytes. The selective involvement of these cells suggests that inappropriate UPR activation may play a key role in the pathophysiology of VWM.

© 2006 American Association of Neuropathologists, Inc

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