PT  - JOURNAL ARTICLE
AU  - Yifeng Lin
AU  - Xiaosha Pang
AU  - Guangcun Huang
AU  - Stephanie Jamison
AU  - Jingye Fang
AU  - Heather P. Harding
AU  - David Ron
AU  - Wensheng Lin
TI  - Impaired Eukaryotic Translation Initiation Factor 2B Activity Specifically in Oligodendrocytes Reproduces the Pathology of Vanishing White Matter Disease in Mice
AID  - 10.1523/JNEUROSCI.1373-14.2014
DP  - 2014 Sep 03
TA  - The Journal of Neuroscience
PG  - 12182--12191
VI  - 34
IP  - 36
4099  - http://www.jneurosci.org/content/34/36/12182.short
4100  - http://www.jneurosci.org/content/34/36/12182.full
SO  - J. Neurosci.2014 Sep 03; 34
AB  - Vanishing white matter disease (VWMD) is an inherited autosomal-recessive hypomyelinating disease caused by mutations in eukaryotic translation initiation factor 2B (eIF2B). eIF2B mutations predominantly affect the brain white matter, and the characteristic features of VWMD pathology include myelin loss and foamy oligodendrocytes. Activation of pancreatic endoplasmic reticulum kinase (PERK) has been observed in oligodendrocytes in VWMD. PERK activation in response to endoplasmic reticulum stress attenuates eIF2B activity by phosphorylating eIF2α, suggesting that impaired eIF2B activity in oligodendrocytes induced by VWMD mutations or PERK activation exploit similar mechanisms to promote selective white matter pathology in VWMD. Using transgenic mice that allow for temporally controlled activation of PERK specifically in oligodendrocytes, we discovered that strong PERK activation in oligodendrocytes during development suppressed eIF2B activity and reproduced the characteristic features of VWMD in mice, including hypomyelinating phenotype, foamy oligodendrocytes, and myelin loss. Notably, impaired eIF2B activity induced by PERK activation in oligodendrocytes of fully myelinated adult mice had minimal effects on morphology or function. Our observations point to a cell-autonomous role of impaired eIF2B activity in myelinating oligodendrocytes in the pathogenesis of VWMD.